Metal complexes that contain perfluoroalkyl, process for their production and their use in NMR diagnosis

ABSTRACT

The invention relates to new, monomeric, perfluoroalkyl-substituted metal complexes, processes for their production, and their use in diagnosis and therapy. The compounds according to the invention are suitable especially as in vivo contrast media in nuclear spin tomography (MRT). They can preferably be used as blood-pool agents and as lymphographic agents.

The invention relates to the objects characterized in the claims, i.e.,new, monomeric, perfluoroalkyl-substituted, paramagnetic metal complexesand complex salts, pharmaceutical agents containing these metalcomplexes, processes for their production, and their use as contrastmedia in ¹H-NMR diagnosis and ¹H-NMR spectroscopy, diagnostic radiology,and radiodiagnosis and as radiotherapeutic agents.

Nuclear magnetic resonance (NMR) is now a very extensively used methodof medical diagnosis, used for in vivo imaging, with which vessels ofthe body and body tissue (including tumors) can be visualized bymeasuring the magnetic properties of the protons in the body water. Tothis end, e.g., contrast media are used that produce contrastenhancement in the resulting images or make these images readable byinfluencing specific NMR parameters of the body protons (e.g.,relaxation times T¹ and T²). Mainly complexes of paramagnetic ions, suchas, e.g., gadolinium-containing complexes (e.g., Magnevist^((R))) areused owing to the effect of the paramagnetic ions on the shortening ofthe relaxation times. A measure of the shortening of the relaxation timeis relaxivity, which is indicated in mm⁻¹·sec⁻¹.

Paramagnetic ions, such as, e.g., Gd³⁻, Mn²⁺, Cr³⁺, Fe³⁺ and Cu² ⁺cannot be administered in free form as solutions since they are tootoxic. To make these ions suitable for in vivo use, they are generallycomplexed, which is described for the first time in EP 0 071 564 A1(complexing with aminopolycarboxylic acids, e.g., withdiethylenetriamine-pentaacetic acid [DTPA]). The di-N-methylglucaminesalt of the Gd-DTPA complex is known under the name Magnevist^((R)) andis used, i.a., to diagnose tumors in the human brain and in the kidney.

The meglumine salt of Gd-DOTA (gadolinium(III) complex of1,4,7,10-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) that isdescribed in French Patent 25 39 996 is another contrast medium that hasdemonstrated its value in nuclear spin tomography and was registeredunder the name Dotarem^((R)).

These contrast media cannot be used, however, in a satisfactory mannerfor all applications. Thus, the contrast media used clinically atpresent for the modern imaging processes of nuclear spin tomography(MRI) and computer tomography (CT), such as, e.g., Magnevist^((R)), ProHance^((R)), Ultravist^((R)) and Omniscan^((R)), are dispersed into theentire extracellular space of the body (in the intravascular space andin the interstice).

Contrast media that also are dispersed exclusively in the latter whenadministered in the vascular space and thus label it (so-calledblood-pool agents) are especially desirable, however, to visualizevessels.

An attempt was made to solve these problems by using complexing agents,which are bound to macromolecules or biomolecules. Up until now, thishas had very limited success.

Thus, for example, the number of paramagnetic centers in the complexesthat are described in EP 0 088 695 A1 and EP 0 150 844 A1 is inadequatefor satisfactory imaging.

If the number of required metal ions is increased by repeatedlyintroducing complexing units into a macromolecular biomolecule, this isassociated with an intolerable impairment of the affinity and/orspecificity of this biomolecule [J. Nucl. Med. 24, 1158 (1983)].

Macromolecular contrast media for angiography, such as albumin-Gd-DTPA,are described in Radiology 1987; 162: 205. Twenty-four hours afterintravenous injection in rats, however, albumin-Gd-DTPA shows aconcentration in the liver tissue that amounts to almost 30% of thedose. In addition, only 20% of the dose is eliminated within 24 hours.

The macromolecule polylysine-Gd-DTPA (EP 0 233 619 A1) can also be usedas a blood-pool agent. For production reasons, however, this compoundconsists of a mixture of molecules of various sizes. In excretion testsin rats, it was shown that this macromolecule is excreted unaltered byglomerular filtration via the kidney. For synthesis reasons, it containspolylysine-Gd-DTPA but also macromolecules that are so large that theycannot pass through the capillaries of the kidney in the case ofglomerular filtration and thus remain in the body.

Macromolecular contrast media based on carbohydrates, e.g., dextran,have also been described (EP 0 326 226 A1). The drawback of thesecompounds lies in the fact that the latter generally have only about 5%of the signal-enhancing paramagnetic cation.

The object of the invention was therefore to make available new ¹H-NMRcontrast media that do not exhibit the above-mentioned drawbacks andespecially show a higher proton relaxivity and thus allow a reduction ofthe dose with increased signal intensity. The contrast media are also tobe stable, well compatible and mainly exhibit organ-specific properties,whereby, on the one hand, their retention in the organs to be studied isto be sufficient to obtain the number of images that is necessary for anunambiguous diagnosis at low dosage, but, on the other hand, anexcretion of metals from the body that is as fast as possible and verylargely complete is then to be ensured.

The object of the invention is achieved with the monomeric,perfluoroalkyl-containing compounds of general formula I according toclaim 1, which show a surprisingly high proton relaxivity of 20-50[mM⁻¹·sec⁻¹, 39° C., 0.47 T]. In comparison with this, proton relaxivityfor commercially available ¹H-NMR contrast media Magnevist^((R)),Dotarem^((R)), Omniscan^((R)) and Pro Hance^((R)) is between 3.5-4.9[mM⁻¹·sec⁻¹, 39° C., 0.47 T].

In addition, the compounds according to the invention are extremely wellsuited for detecting and locating vascular diseases, since they are alsoexclusively dispersed in the latter when administered in theintravascular space. The compounds according to the invention make itpossible to distinguish tissue that is well-supplied with blood fromtissue that is poorly supplied with blood with the aid of nuclear spintomography and thus to diagnose an ischemia. Infarcted tissue can alsobe delimited from surrounding healthy or ischemic tissue due to itsanemia, if the contrast media according to the invention are used. Thisis of special importance if the point is, e.g., to distinguish amyocardial infarction from an ischemia.

Compared to the macromolecular compounds that were previously used asblood-pool agents, such as, for example, Gd-DTPA polylysine, thecompounds according to the invention also show a higher T¹ relaxivity(see Tab. 3) and are thus distinguished by a large increase in signalintensity in the case of NMR imaging. Since, in addition, they have anextended retention in the blood space, they can also be administered inrelatively small dosages (of, e.g., ≦50 μmol of Gd/kg of body weight).Mainly, however, the compounds according to the invention, none of whichare polymeric compounds, are eliminated quickly and almost completelyfrom the body.

It was also shown that the compounds of this invention are suitable notonly as blood-pool agents, but are also excellent lymph-specific MRTcontrast media (lymphographic agents).

The visualization of the lymph nodes is of vital importance for earlydetection of metastatic invasions in cancer patients. The contrast mediaaccording to the invention allow small metastases in non-enlarged lymphnodes (<2 cm) to be distinguished from lymph node hyperplasias withoutmalignant invasions. In this case, the contrast media can beadministered intravascularly or interstitially/intracutaneously.Interstitial/intracutaneous administration has the advantage that thesubstance is transported directly from the scattering concentrate table(e.g., primary tumor) via the corresponding lymph tracts into thepotentially affected regional lymph node stations. Likewise, a highconcentration of contrast medium in the lymph nodes can be achieved witha small dose.

The compounds according to the invention meet all requirements that arecalled for by contrast media in indirect MRT lymphography: good localcompatibility, quick elimination of injection site, quick and verylargely complete elimination from the entire organism. They also show ahigh concentration over several lymph node stations and thus make itpossible to make relevant diagnostic statements. Thus, in the guinea pigmodel, it was possible to show a high concentration over several lymphnode stations (popliteal, inguinal, iliac) after s.c. administration(2.5-10 μmol/kg of body weight, injection in the interdigital spaces ofthe hind paw). In especially suitable cases, gadolinium concentrationsof respectively ≧200 or ≧300 μmol/l were obtained in the second(inguinal) and third (iliac) stations. Usually, lymph node concentrationin the range of 100 to 1000 μmol/l can be obtained with the compoundsaccording to the invention.

It was possible to confirm the special suitability of the compoundsaccording to the invention in MR imaging studies in guinea pigs. Thus,120 minutes after subcutaneous administration of 10 μmol/kg of bodyweight of a perfluorine-containing gadolinium complex (guinea pigs, hindpaw, interdigital space) in T¹-weighted spin-echo images (TR 400 ms, TE15 ms), a clear enhancement of the popliteal lymph nodes (270%) as wellas the inguinal lymph nodes (104%) was observed (cf. Image 1).

In humans, the compounds according to the invention can be injectedlocally (either subcutaneously or directly percutaneously in the tissueof interest). Several injection sites (weals) with a respectiveinjection volume of 0.2 to 1 ml are grouped around the areas of interest(e.g., tumor). In this case, the injected total volume should not in anycase exceed 5 ml. This means that in the formulation, a metalconcentration of 75-100 mmol/l must be present, so that a potentialclinical dose of 5-10 μmol/kg of body weight can be administered withthis volume. The site of administration thereof depends on whether aspecific lymph outflow field from the tissue corresponding to it is tobe specifically stained (e.g., in the case of gynecological or rectaltumors), or whether the unknown outflow field of a certain lesion (ergothe area for a possible therapeutic intervention, e.g., with melanoma orcarcinoma of the breast) is to be visualized.

In normal lymph node tissue, where the concentration of the compoundoccurs, gadolinium concentrations of at least 50 μmol/l and at most 2500μmol/l are required for MR imaging. The imaging can be carried out(depending on injection site and tissue) after 30 minutes or up to 4-6hours after injection of the compounds according to the invention. Sincemainly the T¹ relaxation times of the protons of the water of the lymphnode tissue are influenced with the compounds of gadolinium complexesaccording to the invention, T¹-weighted sequences are best able toidentify an MRT enhancement of the lymph node stations. Since lymphnodes very frequently are embedded in fatty tissue, and the latter has avery high signal intensity in such sequences, fat-suppressed measuringmethods suggest themselves. Paramagnetic gadolinium complexes incombination with fat-suppressed, T¹-weighted measuring sequences havethe great advantage, compared to the formulations of superparamagneticiron oxide particles, that they allow MRT images with greater spatialresolution, with fewer distortion artifacts (based on susceptibilityartifacts) and with shorter imaging time.

Since positive labeling of the lymph nodes occurs (i.e., signal rise),MRT images without contrast media for comparison are also no longerabsolutely necessary, and the total examination time per patient can beshortened.

The new perfluoroalkyl-containing compounds of general formula I ofclaim 1 according to the invention comprise both complexing agents andmetal complexes. Compounds of general formula I with Z¹ as hydrogen atomare referred to as complexing agents and compounds with at least one ofpossible substituents Z¹ as metal ion equivalent are referred to asmetal complexes.

The compounds of general formula I according to the invention contain,as preferred radical L, the following:

According to the invention, radicals L of the compounds mentioned in theexamples of this description of the invention are quite especiallypreferred. other preferred compounds are those in which X of the formula—C_(n)F_(2n)X means fluorine, and n stands for the numbers 4 to 15.

Compounds of general formula I with A in the meaning of general formulaIX, whereby L contains at least one —NHCO group, can be obtained fromcompounds of general formula 14

in which

-   -   R³ is in the above-mentioned meaning, Z¹ is in the meaning of a        metal ion equivalent of atomic numbers 21-29, 39, 42, 44 or        57-83, and    -   M¹ is in the meaning of L, by reaction with compounds of general        formula 15        in which    -   R^(F) has the above-mentioned meaning,    -   M² is in the meaning of L and    -   Nu is in the meaning of a nucleofuge.

Advantageously used as nucleofuges are the radicals:

-   -   Cl, F, —OTs, —OMs,

The reaction is carried out in a mixture of water and organic solventssuch as: isopropanol, ethanol, methanol, butanol, dioxane,tetrahydrofuran, dimethylformamide, dimethylacetamide, formamide ordichloromethane. Preferred are ternary mixtures consisting of water,isopropanol and dichloromethane.

The reaction is carried out at a temperature interval between −10°C.-100° C., preferably between 0° C.-30° C.

As acid traps, inorganic and organic bases such as triethylamine,pyridine, N-methylmorpholine, diisopropylethylamine,dimethylaminopyridine, alkali and alkaline-earth hydroxides, theircarbonates or bicarbonates such as lithium hydroxide, sodium hydroxide,potassium hydroxide, sodium carbonate, sodium bicarbonate, potassiumbicarbonate are used.

The compounds of general formula 15 are obtained from compounds ofgeneral formula 16HO₂C-M²-R^(F)   (16)in which

-   -   R^(F), M² have the above-mentioned meaning, according to the        processes of acid activation that are generally known to one        skilled in the art, such as by reaction of the acid with        dicyclohexylcarbodiimide,        N-hydroxysuccinimide/dicyclohexylcarbodiimide,        carbonyldiimidazole,        2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, oxalic acid        dichloride or isobutyl chloroformate according to the processes        described in the literature:        -   Aktivierung von Carbonsäuren [Activation of Carboxylic            Acids]. Übersicht in Houben-Weyl, Methoden der Organischen            Chemie [Survey in Houben-Weyl, Methods of Organic            Chemistry], Volume XV/2, Georg Thieme Verlag Stuttgart, 19.        -   Aktivierung mit Carbodiimiden [Activation with            Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46: 1550            (1963).        -   E. Wünsch et al., Volume 100: 173 (1967).        -   Aktivierung mit Carbodiimiden/Hydroxysuccinimid (Activation            with Carbodiimides/Hydroxysuccinimide]: J. Am. Chem. Soc.            86: 1839 (1964) as well as J. Org. Chem. 53: 3583 (1988).            Synthesis 453 (1972).        -   Anhydridmethode,            2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride            Method, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: B.            Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz            et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J. R.            Voughn, Am. Soc. 73: 3547 (1951).        -   Imidazolid-Methode [Imidazolide Method]: B. F. Gisin, R. B.            Menifield, D. C. Tosteon, Am. Soc. 91: 2691 (1969).        -   Säurechlorid-Methoden, Thionylchlorid [Acid Chloride            Methods, Thionyl Chloride]: Helv., 42: 1653 (1959).        -   Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29: 843            (1964).

The compounds of general formula 16 are commercially available products(Fluorochem, ABCR) or are obtained from compounds of general formula 17H-Q-M³-R^(F)   (17)with

-   -   M³ in the meaning of L and    -   Q in the meaning of oxygen, sulfur, a >CO group, >N—R³, R³—N—SO₂        with a bonding of a nitrogen atom to a hydrogen atom,    -   by reaction with compounds of general formula 18        with    -   Hal meaning Cl, Br, I and    -   R⁴ meaning H, methyl, ethyl, t-butyl, benzyl, isopropyl,        represented, for example, according to C. F. Ward, Soc. 121,        1161 (1922), according to the methods known to one skilled in        the art, such as alkylation of alcohols with alkyl halides        [Houben-Weyl, Methoden der Organischen Chemie,        Sauerstoffverbindungen [Oxygen Compounds] I, Part 3, Methoden        zur Herstellung und Umwandlung von Ethern (Methods for the        Production and Conversion of Ethers], Georg Thieme Verlag,        Stuttgart 1965, Alkylierung von Alkoholen mit Alkylhalogeniden        [Alkylation of Alcohols with Alkyl Halides], p. 24, Alkylierung        von Alkoholen mit Alkylsulfaten [Alkylation of Alcohols with        Alkyl Sulfates] p. 33] or N-Alkylierung eines Sulfonamids mit        Alkylsulfonaten [N-Alkylation of a Sulfonamide with        Alkylsulfonates] (Houben-Weyl, Methoden der organischen Chemie,        XI/2 Stickstoffverbindungen [XI/2 Nitrogen Compounds], Georg        Thieme Verlag Stuttgart, 1957, p. 680; J. E. Rickman and T.        Atkins, Am. Chem. Soc., 96: 2268, 1974, 96: 2268; F. Chavez        and A. D. Sherry, J. Org. Chem. 1989, 54: 2990].

If Q means a >CO group, the reaction is performed with a Wittig reagentof the structure

whereby r means numbers 0-16.

The —CH═CH double bond that is produced in this case can remain as acomponent of the structure or be converted to a —CH₂—CH₂ group bycatalytic hydrogenation (Pd 5%/C).

The compounds of general formula 18 are commercially available products(Fluorochem, ABCR).

As an alternative, compounds of general formula I with A in the meaningof general formula IX can be obtained from compounds of general formula19

with

-   -   R^(F), R³ and R⁴ in the above-mentioned meaning and    -   L′ in the meaning of L, optionally with protected hydroxyl or        carboxyl functions,        by, if necessary, protective groups that are present being        cleaved and the thus obtained complexing agents being reacted        with metal oxides or metal salts at room temperature or elevated        temperature with the methods known according to one skilled in        the art (EP 250358, EP 255471), and then—if desired—acid        hydrogen atoms that are present being substituted by cations of        inorganic and/or organic bases, amino acids or amino acid        amides.

The compounds of general formula 19 are obtained from compounds ofgeneral formula 20 (D03A or the esters)

with

-   -   R⁴ in the above-mentioned meaning        by reaction with compounds of general formula 21        in which    -   R³ has the meaning of R¹, optionally in protected form, or        —(CH₂)_(m)-L′-R^(F), whereby m is 0, 1 or 2, and L′ and R^(F)        have the above-mentioned meaning. The reaction is carried out in        alcohols such as methanol, ethanol, isopropanol, butanol, ethers        such as dioxane, tetrahydrofuran, dimethoxy ethers or in water        or in mixtures of water and one of the mentioned organic        solvents, as well as also acetonitrile, acetone,        dimethylformamide, dimethylacetamide or dimethyl sulfoxide,        dichloromethane, dichloroethane, chloroform at temperatures        between −10° C. and 180° C., preferably at 20°-100° C. The        addition of organic or inorganic bases, such as triethylamine,        pyridine, dimethylaminopyridine, N-methylmorpholine,        diisopropylamine, alkali or alkaline-earth hydroxides or their        carbonates or bicarbonates such as lithium hydroxide, sodium        hydroxide, potassium hydroxide, sodium carbonate, potassium        carbonate, sodium bicarbonate, potassium bicarbonate has proven        advantageous. In the case of low-boiling epoxides, the reaction        is carried out in an autoclave.

The compounds of general formula 21 are commercially available products(Fluorochem, ABCR) or can be obtained from compounds of general formula22R³—CH═CH-L′-R^(F)   (22)by epoxidation according to the methods known to one skilled in the art,for example, the wolframate-catalyzed oxidation with H₂O₂ according toPayne, the cyclization of halohydrins or the alkaline H₂O₂ oxidation inthe presence of nitrites.

Especially suitable for this reaction is 3-chloroperbenzoic acid indichloromethane at room temperature. Houben-Weyl, Methoden derOrganischen Chemie, Sauerstoffverbindungen I, Part 3, Methoden zurHerstellung und Umwandlung dreigliedriger cyclische Ether (1,2-Epoxide)(Methods for the Production and Conversion of Three-Membered CyclicEthers (1,2-Epoxides)], Georg Thieme Verlag, Stuttgart, 1965; G. B.Payne and P. H. Williams, J. Org. Chem., 159, 24: 54; Y. Ogata and Y.Samaki, Tetrahedron 1964, 20: 2065; K. B. Sharpless et al., Pure Appl.Chem. 55, 589 (1983).

Compounds of general formula 22 are preferably obtained by Wittigreaction, or by the variants according to Horner, Schlosser or Bestmann,Houben-Weyl, Methoden der Organischen Chemie XII/1, OrganischePhosphorverbindungen Teil 1 [Organic Phosphorus Compounds Part 1], GeorgThieme Verlag, Stuttgart, 1963, Phosphoniumsalze [Phosphonium Salts] p.79, Phosphoniumylide [Phosphonium Ylides] p. 112, Wittig Reaction p.121; A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley & Sons,Inc., New York, Chichester, Brisbane, Toronto, Singapore, 1993, WittigReaction p. 221; Schlosser-Modifikation der Wittig-Reaktion [SchlosserModification of the Wittig Reaction] p. 240; Wadsworth-Emmons-Reaktion[Wadsworth-Emmons Reaction] p. 313; Horner Reaktion [Horner Reaction] p.362, by reaction of a triarylphosphonium ylide

with L′ and R^(F) in the above-mentioned meaning and Ar meaning aryl,especially phenyl, with commercially available methods (Merck, Fluka) oraccording to the methods known to one skilled in the art, for example,oxidation of primary alcohols with chromium trioxide/pyridine,Houben-Weyl, Methoden der organischen Chemie, Sauerstoffverbindungen II,Part 1, Aldehyde [Aldehydes], Georg Thieme Verlag, Stuttgart, 1954,aldehydes of general formula 20 that can be producedOHC—R³   (24)whereby

-   -   R³ can also be H.

Triarylphosphonium ylides 23 are produced from the corresponding halidesof general formula 25Hal-CH₂-L′-RF   (25)with Hal, L′ and RF in the above-mentioned meaning according to themethods known to one skilled in the art, for example by heating thetriarylphosphine with the alkylhalide, Houben-Weyl, Methoden derOrganischen Chemie XII/1, Organische Phosphorverbindungen Teil 1, GeorgThieme Verlag, Stuttgart, 1963 or A. W. Johnson, Ylides and Imines ofPhosphorus, John Wiley & Sons, Inc., New York, Chichester, Brisbane,Toronto, Singapore, 1993. The compounds of general formula 25 arecommercially available products (Fluorochem, ABCR, 3M).

The compounds of general formula 21 with R³═H are preferably obtainedfrom compounds of general formula 17H-Q′-M³-R^(F)   (17)in which

-   -   Q′ is in the meaning of Q, but cannot mean any >CO group,    -   M³ has the meaning of L with the exception of the direct bond        and    -   R^(F) has the above-mentioned meaning,        by reaction according to the way of etherification or        sulfonamidealkylation with epihalohydrins that is known to one        skilled in the art: (Houben-Weyl, Methoden der Organischen        Chemie, Sauerstoffverbindungen I, Part 3, Methoden zur        Herstellung und Umwandlung von Ethern, Georg Thieme Verlag,        Stuttgart, 1965, Alkylierung von Alkoholen (Alkylation of        Alcohols], p. 24, 33; Houben-Weyl, Methoden der Organischen        Chemie, XI/2 Stickstoffverbindungen, Georg Thieme Verlag,        Stuttgart, 1957, p. 680; J. E. Rickman and T. J. J. Atkins, Am.        Chem. Soc. 1974, 96: 2268; F. Chavez and A. D. Sherry, 1989,        54: 2990) of general formula 26        with    -   Hal′ in the meaning of Hal, F, —OTs, OMs.

In the case of low-boiling epoxides, the reaction is carried out in anautoclave.

Compounds of general formula I with A in the meaning of general formulaVIII are obtained from compounds of general formula 27

with R², R³, R⁴, L′ and R^(F) in the above-mentioned meaning, bycleavage of optionally present protective groups and complexing in theway known to one skilled in the art.

Compounds of general formula 27 are obtained by alkylation of thecompounds of general formula 20 with compounds of general formula 28

in which Hal, R², R³, L′ and R^(F) have the above-mentioned meaning, ina way known in the art, for example as described under EP 0 232 751 B1(Squibb).

Compounds of general formula 28 are produced from compounds of generalformula 29

with L′, R³ and R^(F) in the above-mentioned meaning and an activatedhalocarboxylic acid of general formula 30

with Nu, R² and Hal in the above-mentioned meaning according to themethods of amide formation via activated carboxylic acids that are knownto one skilled in the art [cf. Lit. p. 11].

Compounds of general formula 30 can be obtained from the acids accordingto C. Hell, Vol. 14: 891 (1881); J. Volhard, A 242, 141 (1887); N.Zelinsky, Vol. 20: 2026, (1887) or from the haloacids according to theactivation methods as they are described in general formula 15.

The compounds of general formula 29 can be easily produced according tothe methods of amine synthesis that are known to one skilled in the art[Houben-Weyl, Methoden der Organischen Chemie, StickstoffverbindungenII, Amino, 1st Run, Georg Thieme Verlag, Stuttgart, 1957] from thecommercially available compounds (Fluorochem, ABCR) of general formula31Hal-CH₂CH₂-L′-R^(F)   (31)or 32HO—CH₂CH₂-L′-R^(F)   (32)for example, by alkylation of a compound 31 with an amine PhCH₂NHR³ andsubsequent deprotection of the amino group by catalytic hydrogenation orby Mitsunobu reaction (H. Loibner and E. Zbiral, Helv. 59, 2100 (1976),A. K. Bose and B. Lal, Tetrahedron Lett. 3973 (1973)] of a compound 32with potassium phthalimide and deprotection with hydrazine hydrate.

Compounds of general formula I with A in the meaning of general formulaVII are obtained from compounds of general formula 33

with

-   -   L′, R^(F) and R⁴ in the above-mentioned meaning and    -   Y′ in the meaning of Y, optionally with protective groups, by        cleavage of optionally present protective groups and complexing        according to the methods that are known to one skilled in the        art (Protective Groups in Organic Synthesis, 2nd Edition, T. W.        Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York,        1991; EP 0 130 934, EP 0 250 358).

Compounds of general formula 33 are obtained from compounds of generalformula 20 and compounds of general formula 34

in which

-   -   Hal′, L′, R^(F) have the above-mentioned meaning and Y′ stands        for the radical        in a way known in the art, for example as described in EP 0 232        751 B1, EP 0 292 689 A2 (both Squibb) or EP 0 255 471 A1        (Schering).

The production of compounds of general formula 34 is carried outaccording to known methods, for examples according toHell-Volhard-Zelinsky from commercially available precursors (ABCR).

Compounds of general formula I with A in the meaning of general formulaVI are obtained from compounds of general formula 35

in which L′, R⁴ and R^(F) have the above-mentioned meaning, by, ifappropriate, cleavage of protective groups and complexing in a way knownin the art [Protective Groups in Organic Synthesis, 2nd edition, T. W.Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York, 1991 (EP 0130 934, EP 0 250 358)].

Compounds of general formula 35 are obtained by reactingα-halocarboxylic acid esters or α-halocarboxylic acids of generalformula 18 with compounds of general formula 36

with L′ and R^(F) in the above-mentioned meaning, according to themethods that are known to one skilled in the art, as described, forexample, in EP 0 255 471 or U.S. Pat. No. 4,885,363.

Compounds of general formula 36 can be obtained by cleavage ofoptionally present protective groups and subsequent reduction withdiborane according to the known processes from compounds of generalformula 37

in which

-   -   L′, R^(F), o, q, have the above-mentioned meaning and    -   K has the meaning of a protective group.

The compounds of general formula 37 are available by a condensationreaction from an activated, N-protected iminodiacetic acid 38 and amine39:

in which

-   -   L′, R^(F), o, q, Nu and K have the abovementioned meaning. As        nucleofuge, preferably the N-hydroxysuccinimide is used; as        protective group, the benzyloxycarbonyl, trifluoroacetyl or        t-butyloxycarbonyl group is used.

Compounds of general formula 38 can be obtained according to theprocesses of protecting the amino group and of activating carboxylicacid that are known to one skilled in the art [Protective Groups,Activation of Carboxyl Groups, p. 11] with protected iminodiacetic acid40

in which

-   -   K has the meaning of a protective group, from iminodiacetic acid        41

As an alternative, compounds of general formula 36 are available by, ifappropriate, cleavage of protective groups and reduction with diboraneaccording to the process described in 37

from compounds of general formula 42

Compounds of general formula 42 can be obtained by closing the rings ofSecco compounds 43

in which

-   -   L′ and R^(F) have the above-mentioned meaning, according to        standard processes; for example, by reaction with the Mukaiyama        reagent 2-fluoro-1-methylpyridinium-tosylate        [J. Org. Chem. 1994, 59, 415; Synthetic Communications 1995, 25,        1401] or with the phosphoric acid diphenylester-azide        [J. Am. Chem. Soc. 1993, 115, 3420; WO 94/15925].

Compounds of general formula 43 are available according to the describedprocesses by condensation of activated acid 44

with Nu and K in the above-mentioned meaning, with a compound of generalformula 45

in which

-   -   L′, R⁴ and R^(F) have the above-mentioned meaning.

Compounds of general formula 44 are available from commerciallyavailable triglycine (Bachem, Fluka) 46

by protection of the amino group with subsequent activation of the acidfunction according to the processes for amine protection and carboxylicacid reactivation that are known to one skilled in the art (Lit. p. 12).

The compounds of general formula 45 can be easily obtained fromcompounds of general formula 62 by introducing protective group R⁴according to the methods known to one skilled in the art—for example,re-esterification of a sulfite ester.

Compounds of general formula I with A in the meaning of general formulaII are obtained from compounds of general formula 47

with L′, R³, R⁴, R^(F) and Y′ in the above-mentioned meaning, by, ifappropriate, cleavage of protective groups and complexing in a way thatis well-known to one skilled in the art (Protective Groups, EP 0 250358, EP 0 130 934).

If Y′ in general formula 47 means an OH group, the compounds areobtained by reacting a compound 48

with R⁴ in the above-mentioned meaning, produced according to DE 3 633243, with an amine of general formula 29 under the conditions alreadydescribed and subsequent cleavage of the protective groups.

If Y′ in formula 47, however, is the group

then the reaction is performed under analogous conditions withDTPA-bisanhydride (commercially available product, Merck) 49

Compounds of general formula I, with A in the meaning of general formulaIII, are obtained from compounds of general formula 50

in which

-   -   L′, R², R³, R⁴ and R^(F) have the above-mentioned meaning, by,        if appropriate, cleavage of protective groups and complexing in        a way that is well-known to one skilled in the art [Protective        Groups, EP 0 071564, EP 0 130 934, DE-OS 3 401 052].

Compounds of general formula 50 are obtained according to the processdescribed in J. Org. Chem. 1993, 58: 1151 from compounds of generalformula 51

and halocarboxylic acid derivatives of formula 52

in which R⁴ and Hal have the already described meaning. The compounds ofgeneral formula 51 are produced by acylation of an amine of generalformula 29 with an activated N-protected amino acid of general formula53

in which Nu has the above-mentioned meaning and K is in the meaning of aprotective group such as Z, —BOC, FMOC, —COCF₃, and subsequent cleavageof the protective group.

Compounds of general formula I with A in the meaning of general formulaIV are obtained from compounds of general formula 54

in which

-   -   L′, R^(F) and R⁴ have the above-mentioned meaning, by, if        appropriate, cleavage of the protective groups and completing        according to a method that is known to one skilled in the art,        as already described [Protective Groups, EP 0 071 564, EP 0 130        934, DE-OS 3 401 052].

Compounds of general formula 54 can be obtained in a known way from thehalogen compounds of general formula 55Hal-L′-RF   (55)that can be obtained as commercially available products (Fluorochem,ABCR) by reaction with hydroxy acids 56

in which

-   -   R⁴ has the above-mentioned meaning. The compounds of formula 56        can be obtained in a way known in the art according to J. Org.        Chem. 58, 1151 (1993) from commercially available serine ester        57 (Bachem, Fluka)        with R⁴ in the above-mentioned meaning and halocarboxylic acid        esters 58

Compounds of general formula I with A in the meaning of general formulaV are obtained from compounds of general formula 59

in which

-   -   L′, o, q, R⁴ and R^(F) have the above-mentioned meaning, by, if        appropriate, cleavage of protective groups and complexing        according to a method that is known to one skilled in the art.        [Protective Groups, EP 0 071 564, EP 0 130 934, DE-OS 3 401        052].

Compounds of general formula 59 can be produced in a known way, forexample, according to J. Org. Chem., 58, 1151 (1993), by reaction ofhalocarboxylic acid esters 19Hal-CH₂CO₂R⁴   (18)with Hal and R⁴ in the above-mentioned meaning, and a compound ofgeneral formula 39

in which

-   -   L′, o, q, and R^(F) have the above-mentioned meaning.

The compounds of general formula 39 are obtained for the case q=0 fromthe compounds of general formula 60

with

-   -   L′, R^(F) and K in the above-mentioned meaning, in a way known        in the art [Helv. Chim. Acta, 77: 23 (1994)] by reduction with        diborane and cleavage of the protective groups. The compounds of        general formula 60 are obtained with ethylenediamine by        aminolysis of the activated compounds of general formula 61        in which    -   L′, Nu, R^(F) and K have the above-mentioned meaning.

The compounds of general formula 61 are produced according to the knownmethods of protective group chemistry [Protective Groups] from theunprotected acid of general formula 62

specifically the amino group is protected in a first step, followed bythe activation of the acid group in the second step.

The compounds of general formula 62 can be produced according to themethods of amino acid synthesis [Houben-Weyl, Methoden der organischenChemie, XI/2 Stickstoffverbindungen II and III, II Aminosäuren [II AminoAcids]; Georg Thieme Verlag Stuttgart, 1958, Strecker-Reaktion [StreckerReaction], p. 305; Erlenmeyer-Reaktion [Erlenmeyer Reaction], p. 306;Aminolyse von α-Halogencarbonsäuren [Aminolysis of α-HalocarboxylicAcids], p. 309] from the commercially available aldehydes of generalformula 63HOC-L′-R^(F)   (63)for example, according to Strecker, via the azlactone or via thecyanohydrin.

The compounds of general formula 39 are obtained for the case o=0 fromthe compounds of general formula 64

with R^(F), L′ and K in the mentioned meanings, in a way known in theart by cleavage of the protective groups and reduction with diborane.

Compounds of general formula 64 are available by aminolysis ofN-protected activated glycines 53 with compounds of general formula 65

in which R^(F) and L′ have the mentioned meanings.

The compounds of general formula 65 can be obtained in a simple way fromcompounds of general formula 61 by amide formation with ammonia andsubsequent cleavage of the protective group.

Compounds of general formula XIII can be produced analogously to thecompounds of general formula III, by halocarboxylic acid derivatives ofgeneral formula 52 being reacted with a compound of general formula 66

in which R^(F), L′ and R² have the above-mentioned meanings.

The compounds of general formula 66 are produced by reaction of acompound of general formula 67

with the activated, N-protected amino acid of general formula 53analogously to the reaction of amine 29 with compound 53.

The compounds of general formula 67 can be obtained by reaction ofpiperazine—freely or optionally partially protected—withperfluoroalkylsulfonic acid fluorides or -chlorides. (The sulfonamideformation from amine and sulfofluoride is described in DOS 2 118 190,DOS 2 153 270, both Bayer AG).

Compounds of general formula XI with q meaning the numbers 0 or 1 areproduced analogously to compounds of general formula VIII, by compoundsof general formula 20 being reacted with compounds of general formula 68

in which R^(F), L′, R² and Hal have the above-mentioned meaning or beingreacted with compounds of general formula 68a

in which R^(F), L′, R², p and Hal have the above-mentioned meanings.

Compounds of general formula 68 can be obtained from compounds ofgeneral formula 30 and piperazine derivatives of general formula 67 in away known in the art.

Compounds of general formula XII are produced analogously to compoundsof general formula II, e.g., by reaction of compounds of formula 49 withpiperazine derivatives of general formula 67.

Compounds of general formula 68a are produced from compounds of generalformula 67 by amide-coupling with compounds of general formula 68b

Compounds of general formula I with A in the meaning of general formulaX are obtained from compounds of general formula 69

in which41a

-   -   L′, R³, R⁴ and R^(F) have the above-described meaning and Sg is        in the meaning of a protective group, by, if appropriate,        cleavage of protective groups and complexing in a way known in        the art [Protective Groups in Organic Synthesis, 2nd        Edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons,        Inc., New York, 1991 (EP 0 130 934, EP 0 250 358)].

Compounds of general formula 69 are obtained by reaction ofα-halocarboxylic acid esters or α-halocarboxylic acids of generalformula 18 with compounds of general formula 70

with L′, R^(F), R³ and Sg in the above-mentioned meaning according tothe methods that are known to one skilled in the art, as described, forexample, in EP 0 255 471 or U.S. Pat. No. 4,885,363.

Compounds of general formula 70 can be obtained by cleavage ofoptionally present protective groups and subsequent reduction withdiborane according to the known processes from compounds of generalformula 71

in which

-   -   L′, R^(F), R³ and Sg have the above-mentioned meaning.

The compounds of general formula 71 can be obtained by a condensationreaction from an activated iminodiacetic acid derivative of generalformula 72 and the diethylenetriamine of formula 73

in which

-   -   L′, R^(F), R³, Sg and Nu have the above-mentioned meaning.    -   N-Hydroxysuccinimide is preferably used as nucleofuge Nu.

Compounds of general formula 72 can be obtained from compounds ofgeneral formula 74

in which

-   -   L′, R^(F) and Sg have the above-mentioned meaning, by activation        of carboxylic acids, as described oh page 11.

Compounds of general formula 74 are obtained by reaction ofα-halocarboxylic acid esters or α-halocarboxylic acids of generalformula 18 with compounds of general formula 75

in which

-   -   L′, R^(F), R³ and Sg have the above-mentioned meaning, whereby        optionally present ester groups are saponified.

Compounds of general formula 75 are obtained from compounds of generalformula 76

in which

-   -   L′, R^(F), R³, Sg and K have the above-mentioned meaning, by        cleavage of protective group K according to the known processes.

Compounds of general formula 76 are obtained from compounds of generalformula 77

in which

-   -   L′, R^(F), R³ and K have the above-mentioned meaning, by        introduction of a protective group Sg in the way known to one        skilled in the art.

Compounds of general formula 77 are obtained from the compounds ofgeneral formula 78

in which

-   -   L′, R^(F) and K have the above-mentioned meaning, according to        the methods that are well-known to one skilled in the art        (Houben-Weyl, Methoden der Organischen Chemie, XIII 2a,        Metallorganische Verbindungen [Organometallic Compounds] , Georg        Thieme Verlag Stuttgart, 1973, p. 285 ff, Umsetzung        magnesiumorganischer Verbindungen mit Aldehyden [Reaction of        Magnesium-organic Compounds with Aldehydes]; p. 809 ff,        Umsetzung von zinkorganischen Verbindungen mit Aldehyden        [Reaction of Zinc-organic Compounds with Aldehydes];        Houben-Weyl, Methoden der Organischen Chemie XIII/1,        Metallorganische Verbindungen, Georg Thieme Verlag Stuttgart,        1970; p. 175 ff, Umsetzung lithiumorganischer Verbindungen mit        Aldehyden [Reaction of Lithium-organic Compounds with Aldehydes]        by reaction with the organometallic compounds, such as        magnesium, lithium or zinc compounds, that can be obtained from        compounds of general formula 79        Hal-R³   (79)        in which    -   Hal and R³ have the above-mentioned meaning.

Compounds of general formula 79 are commercially available products(ABCR, Fluka).

Compounds of general formula 78 are produced from compounds of generalformula 80

in which

-   -   L′, R^(F) and K have the above-mentioned meaning, by reduction        with diisobutylaluminum hydride (Tett. Lett., 1962, 619; Tett.        Lett., 1969, 1779; Synthesis, 1975, 617).

Compounds of general formula 80 are produced from compounds of generalformula 45

in which

-   -   L′ and R^(F) have the above-mentioned meaning, in a way known to        one skilled in the art by introducing protective group K.

The neutralization of optionally still present free carboxy groups isdone with the aid of inorganic bases (for example, hydroxides,carbonates or bicarbonates) of, for example, sodium, potassium, lithium,magnesium or calcium and/or organic bases such as, i.a., primary,secondary and tertiary amines, such as, for example, ethanolamine,morpholine, glucamine, N-methylglucamine and N,N-dimethylglucamine, aswell as basic amino acids, such as, for example, lysine, arginine andornithine or of amides of originally neutral or acidic amino acids.

To provide neutral complex compounds, enough of the desired bases can beadded, for example, to the acid complex salts in aqueous solution orsuspension to ensure that the neutral point is reached. The solutionobtained can then be evaporated to dryness in a vacuum. Often, it isadvantageous to precipitate the neutral salts formed by addingwater-miscible solvents, such as, for example, lower alcohols (methanol,ethanol, isopropanol and others), lower ketones (acetone and others),polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane and others)and to obtain easily isolated and readily purified crystallizates. Ithas proven especially advantageous to add the desired base as early asduring the complexing of the reaction mixture and thus to save a processstep.

Pharmaceutical agents that contain at least one physiologicallycompatible compound of general formula I, optionally with the additivesthat are commonly used in galenicals, are also the object of theinvention.

The production of the pharmaceutical agents according to the inventionis carried out in a way known in the art, by the complex compoundsaccording to the invention—optionally with the addition of the additivesthat are commonly used in galenicals—being suspended or dissolved inaqueous medium and then the suspension or solution optionally beingsterilized. Suitable additives are, for example, physiologicallyharmless buffers (such as, for example, tromethamine), additives ofcomplexing agents or weak complexes (such as, for example,diethylenetriaminepentaacetic acid or the Ca complexes that correspondto the metal complexes according to the invention) or—ifnecessary—electrolytes, such as, for example, sodium chloride or—ifnecessary—antioxidants such as, for example, ascorbic acid.

If suspensions or solutions of the agents according, to the invention inwater or physiological salt solution are desired for enteral orparenteral administration or other purposes, they are mixed with one ormore adjuvant(s) that are commonly used in galenicals (for example,methylcellulose, lactose, mannitol] and/or surfactant(s) [for example,lecithins, Tween^((R)), Myrj^((R))] and/or flavoring substance(s) fortaste correction [for example, ethereal oils].

In principle, it is also possible to produce the pharmaceutical agentsaccording to the invention without isolating the complexes. In any case,special care must be used to undertake the chelation so that thecomplexes according to the invention are practically free fromnoncomplexed metal ions that have a toxic effect.

This can be ensured, for example, with the aid of color indicators suchas xylenol orange by control titrations during the production process.The invention therefore also relates to the process for the productionof complex compounds and their salts. As a final precaution, thereremains purification of the isolated complex.

The pharmaceutical agents according to the invention preferably contain0.1 μmol-1 mol/l of the complex and are generally dosed in amounts of0.0001-5 mmol/kg. They are intended for enteral and parenteraladministration. The complex compounds according to the invention areused

-   -   1. for NMR diagnosis and diagnostic radiology in the form of        their complexes with the ions of elements with atomic numbers        21-29, 39, 42, 44 and 57-83;    -   2. for radiodiagnosis and radiotherapy in the form of their        complexes with the radioisotopes of the elements with atomic        numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 and 77.

The agents according to the invention meet the varied requirements forsuitability as contrast media for nuclear spin tomography. Thus, afteroral or parenteral administration and by increasing the signalintensity, they are extremely well suited to improve in its informativevalue the image obtained with the aid of the nuclear spin tomograph.They also show the high effectiveness that is necessary to burden thebody with the smallest possible amounts of foreign substances, and thegood compatibility that is necessary to maintain the noninvasive natureof the studies.

The good water-solubility and low osmolality of the agents according tothe invention make it possible to produce highly-concentrated solutions,thus to keep the volume burden of the circulatory system withinjustifiable limits and to offset the dilution by the bodily fluid. Inaddition, the agents according to the invention exhibit not only highstability in vitro, but also surprisingly high stability in vivo, sothat a release or an exchange of the ions that are bound to thecomplexes—and toxic in themselves—is carried out only extremely slowlywithin the time in which the new contrast media are completelyeliminated again.

In general, the agents according to the invention for use as NMRdiagnostic agents are dosed in amounts of 0.0001-5 mmol/kg, preferably0.005-0.5 mmol/kg. Especially low dosages (below 1 mg/kg of body weight)of organ-specific NMR diagnostic agents can be used, for example, fordetecting tumors and myocardial infarctions.

The complex compounds according to the invention can also be usedadvantageously as susceptibility reagents and as shift reagents for invivo NMR spectroscopy.

The agents according to the invention are also suitable asradiodiagnostic agents owing to their advantageous radioactiveproperties and the good stability of the complex compounds that arecontained in them. Details of such use and dosage are described, e.g.,in “Radiotracers for Medical Applications,” CRC Press, Boca Raton, Fla.

The compounds and agents according to the invention can also be used inpositron emission tomography, which uses positron-emitting isotopes suchas, e.g., ⁴³Sc, ⁴⁴Sc, ⁵²Fe, ⁵⁵Co and ⁶⁸Ga (Heiss, W. D.; Phelps, M. E.;Positron Emission Tomography of Brain, Springer Verlag Berlin,Heidelberg, New York 1983).

The compounds according to the invention are also suitable, surprisinglyenough, for differentiating malignant and benign tumors in areas withoutblood-brain barriers.

They are also distinguished in that they are eliminated completely fromthe body and are thus well compatible.

Since the substances according to the invention accumulate in malignanttumors (no diffusion in healthy tissue, but high permeability of tumorvessels), they can also assist the radiation therapy of malignanttumors. The latter are distinguished from the corresponding diagnosisonly by the amount and type of isotopes used. In this case, the aim isthe destruction of tumor cells by high-energy shortwave radiation withas small a range of action as possible. For this purpose, interactionsof the metals that are contained in the complexes (such as, e.g., ironor gadolinium) with ionizing radiations (e.g., x rays) or with neutronrays are employed. The local radiation dose at the site where the metalcomplex is located (e.g., in tumors), is significantly enhanced by thiseffect. To produce the same radiation dose in malignant tissue, theradiation exposure for healthy tissue can be considerably reduced andthus burdensome side effects for the patients can be avoided when suchmetal complexes are used. The metal complex conjugates according to theinvention are therefore also suitable as radiosensitizing substances inthe case of radiation therapy of malignant tumors (e.g., use ofMössbauer effects or in the case of neutron capture therapy). Suitableβ-emitting ions are, for example, ⁴⁶Sc, ⁴⁷Sc, ⁴⁸Sc, ⁷²Ga, ⁷³Ga and ⁹⁰Y.Suitable α-emitting ions that exhibit short half-lives are, for example,²¹¹Bi, ²¹²Bi, ²¹³Bi and ²¹⁴Bi, whereby ²¹²Bi is preferred. A suitablephoton- and electron-emitting ion is ¹⁵⁸Gd, which can be obtained from¹⁵⁷Gd by neutron capture.

If the agent according to the invention is specified for use in thevariant of radiation therapy that is proposed by R. L. Mills et al.(Nature Vol. 336, (1988), p. 787], the central ion must be derived froma Mössbauer isotope, such as, for example, ⁵⁷Fe or ¹⁵¹Eu.

In the case of in vivo administration of the agents according to theinvention, the latter can be administered together with a suitablevehicle, such as, for example, serum or physiological common saltsolution and together with another protein such as, for example, humanserum albumin. In this case, the dosage is dependent on the type ofcellular impairment, the metal ion used and the type of imaging method.

The agents according to the invention are usually administeredparenterally, preferably i.v. They can also be administered—as alreadydiscussed—intravascularly or interstitially/intracutaneously, dependingon how the vessels or tissue of the body are to be examined.

The agents according to the invention are extremely well suited as x-raycontrast media, in which case it is especially to be emphasized thatwith them, no signs of the anaphylaxis-like reactions that are knownfrom the iodine-containing contrast media can be detected inbiochemical-pharmacological studies. They are especially valuablebecause of the advantageous absorption properties in the ranges ofhigher tube voltages for digital substraction techniques.

In general, the agents according to the invention for use as x-raycontrast media are dosed, for example, analogously tomeglumine-diatrizoate, in amounts of 0.1-5 mmol/kg, preferably 0.25-1mmol/kg.

Taken overall, it has been possible to synthesize new complexing agents,metal complexes and metal complex salts to open up new possibilities indiagnostic and therapeutic medicine.

The following examples are used for a more detailed explanation of theobject of the invention:

EXAMPLE 1 a) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-aceticacid-t-butyl ester

20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and 15.73 g (113.8mmol) of potassium carbonate are suspended in 200 ml of acetone, and14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is added indrops at 60° C. It is stirred for 3 hours at 60° C. The salts arefiltered out, and the filtrate is evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone=10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 21.66 g (89% of theory) of a waxy colorless solid

Elementary analysis:

Cld: C 29.96 H 2.51 F 50.36 N 2.18 S 5.00

Fnd: C 29.81 H 2.70 F 50.15 N 2.30 S 4.83

b) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-acetic acid

20 g (31.18 mmol) of the title compound of Example 1a) is dissolved in200 ml of trifluoroacetic acid and stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from methanol/ether.

Yield: 17.34 g (95% of theory) of a colorless crystalline solid

Elementary analysis:

Cld: C 24.63 H 1.38 F 55.19 N 2.39 S 5.48

Fnd: C 24.48 H 1.50 F 55.01 N 2.17 S 5.59

c) Gadolinium Complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (17.09 mmol) of the title compound of Example 1b) and 1.97 g (18.79mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 ml ofdimethylformamide/50 ml of chloroform. At 0° C., 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added and stirred for 1 hour at 0° C., thenfor 3 hours at room temperature. It is cooled again to 0° C., and 5.19 g(51.27 mmol) of triethylamine/50 ml of 2-propanol is added. Then, 10.78g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added and stirred for 3hours at room temperature. It is evaporated to dryness, the residue istaken up in a mixture of 200 ml of methanol/100 ml of chloroform, anddicyclohexylurea is filtered out. The filtrate is evaporated to drynessand purified by RP-chromatography (RP-18/mobile solvent: gradientconsisting of water/n-propanol/acetonitrile).

Yield: 16.37 g (78% of theory) of a colorless, vitreous solid

Water content: 7.1%

T₁-relaxivity (L/mmol·sec) at 20 MHz, 37° C.:

41 (water)

49 (human plasma)

Elementary analysis (relative to anhydrous substance):

Cld: C 30.58 H 3.18 F 28.31 Gd 13.78 N 7.37 S 2.81

Fnd: C 30.40 H 3.29 F 28.14 Gd 13.55 N 7.28 S 2.65

d)10-[2-Hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (8.76 mmol) of the title compound of Example 1c) is dissolved in amixture of 100 ml of water/100 ml of ethanol, and 1.73 g (13.71 mmol) ofoxalic acid-dihydrate is added. It is heated for 8 hours to 80° C. It iscooled to 0° C., and precipitated gadolinium oxalate is filtered out.The filtrate is evaporated to dryness, and the residue is purified onRP-18 (RP-18/mobile solvent: gradient consisting ofwater/i-propanol/acetonitrile).

Yield: 8.96 g (94% of theory) of a vitreous solid

Water content: 9.3%

Elementary analysis (relative to anhydrous substance):

Cld: C 35.30 H 3.98 F 32.73 N 8.52 S 3.25

Fnd: C 35.10 H 4.15 F 32.51 N 8.35 S 3.15

e) Manganese Complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(as sodium salt)

5 g (5.07 mmol) of the title compound of Example 1d) is dissolved in 100ml of water, and 0.58 g (5.07 mmol) of manganese(II) carbonate is added.It is stirred for 3 hours at 80° C. The solution is filtered, and thefiltrate is adjusted to pH 7.2 with 1N sodium hydroxide solution, thenit is freeze-dried.

Yield: 5.87 g (quantitative) of a colorless-amorphous powder

Water content: 8.4%

T₁-relaxivity (L/mmol·sec) at 20 MHz, 37° C.:

2.7 (water)

4.2 (human plasma)

Elementary analysis (relative to anhydrous substance):

Cld: C 32.81 H 3.42 F 30.42 Mn 5.17 N 7.92 Na 2.17 S 3.02

Fnd: C 32.62 H 3.57 F 30.21 Mn 5.06 N 7.80 Na 2.01 S 2.90

f) Ytterbium Complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl-sulfonyl)-nonyl]-1,4,7,-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

1.33 g (2.53 mmol) of ytterbium carbonate is added to 5 g (5.07 mmol) ofthe title compound of Example 1d) in 100 ml of water/30 ml of ethanol,and it is stirred for 3 hours at 80° C. The solution is filtered, andthe filtrate is evaporated to dryness in a vacuum.

Yield: 6.36 g (quantitative) of a vitreous solid.

Water content: 7.8%.

Elementary analysis (relative to anhydrous substance):

Cld: C 30.11 H 3.14 F 27.92 N 7.27 S 2.77 Yb 14.96

Fnd: C 30.02 H 3.27 F 27.80 N 7.10 S 2.68 Yb 14.75

g) Dysprosium Complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctyl-sulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

0.95 g (2.53 mmol) of dysprosium oxide is added to 5 g (5.07 mmol) ofthe title compound of Example 1d) in 100 ml of water/30 ml of ethanol,and it is stirred for 3 hours at 80° C. The solution is filtered, andthe filtrate is evaporated to dryness in a vacuum.

Yield: 6.35 g (quantitative) of a colorless, vitreous solid.

Water content: 8.5%.

Elementary analysis (relative to anhydrous substance):

Cld: C 30.39 H 3.17 F 28.18 N 7.33 S 2.80 Dy 14.18.

Fnd: C 30.17 H 3.25 F 28.03 N 7.21 S 2.65 Dy 14.00

EXAMPLE 2 a)13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-Heptadecafluoro-3-oxatridecanoicacid-t-butyl ester

10.51 g (53.9 mmol) of bromoacetic acid-tert-butyl ester is added indrops to a mixture of 10 g (21.55 mmol) of1H,1H,2H,2H-perfluorodecan-1-ol and 0.73 g (2.15 mmol) oftetrabutylammonium hydrogen sulfate in 100 ml of 60% potassium hydroxidesolution/50 ml of toluene while being stirred vigorously at 0° C. It isstirred for 1 hour at 0° C. 200 ml of toluene is added, the aqueousphase is separated and extracted twice with 50 ml of toluene each. Thecombined organic phases are dried on magnesium sulfate and concentratedby evaporation in a vacuum. The residue is chromatographed on silica gel(mobile solvent: hexane/dichlormethane/acetone=20/10/1).

Yield: 9.72 g (78% of theory) of a colorless viscous oil

Elementary analysis:

Cld: C 33.23 H 2.61 F 55.85

Fnd: C 33.09 H 2.78 F 55.71

b)13,13,13,12,12,11,11,10,10,9,9,8,8,7,7,6,6-Heptadecafluoro-3-oxatridecanoicacid

9.0 g (15.56 mmol) of the title compound of Example 2a) is dissolved in180 ml of trifluoroacetic acid and stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from methanol/ether.

Yield: 7.80 g (96% of theory) of a colorless solid

Elementary analysis:

Cld: C 27.60 H 1.35 F 61.85

Fnd: C 27.48 H 1.49 F 61.66

c) Gadolinium Complex of10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.0 g (13.41 mmol) of the title compound of Example 2b) and 1.70 g(14.75 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 30 mlof dimethylformamide/20 ml of chloroform. At 0° C., 3.04 g (14.75 mmol)of dicyclohexylcarbodiimide is added and stirred for 1 hour at 0° C.,then for 3 hours at room temperature. It is cooled again to 0° C., and4.48 g (44.25 mmol) of triethylamine/50 ml of 2-propanol is added. Then,8.46 g (14.75 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,dissolved in 40 ml of water, is added and stirred for 3 hours at roomtemperature. It is evaporated to dryness, the residue is taken up in amixture of 100 ml of methanol/30 ml of chloroform, and dicyclohexylureais filtered out. The filtrate is evaporated to dryness and purified byRP-chromatography (RP-18/mobile solvent: gradient consisting ofwater/n-propanol/acetonitrile).

Yield: 11.8 g (75% of theory) of a colorless, vitreous solid

Water content: 8.2%

T₁-relaxivity (L/mmol·sec) at 20 MHz, 37° C.:

19 (water)

33 (human plasma)

Elementary analysis:

Cld: C 32.32 H 3.27 F 29.96 Gd 14.59 N 6.50

Fnd: C 32.16 H 3.42 F 29.78 Gd 14.39 N 6.40

EXAMPLE 3 a)1,2-Epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecane

7.97 g (86.18 mmol) of epichlorohydrin is added in drops to a mixture of20 g (43.09 mmol) of 1H,1H,2H,2H-perfluorodecan-1-ol and 0.79 g (2.32mmol) of tetrabutylammonium hydrogen sulfate in 200 ml of 60% potassiumhydroxide solution/100 ml of toluene while being stirred vigorously at10° C., and care is taken to ensure that the temperature of the reactionsolution is not higher than 20° C. It is allowed to stir for 2 hours at15° C., and then 3.99 g (43.09 mmol) of epichlorohydrin is added indrops as described above. Then, it is stirred overnight at roomtemperature. 100 ml of methyl-tert-butyl ether is added, and the aqueousphase is separated. The latter is extracted twice more with 50 ml oftoluene each. The organic phases are combined, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The residue ischromatographed on silica gel (mobile solvent:dichloromethane/hexane/acetone=20/10/1).

Yield: 19.05 g (85% of theory) of a colorless oil

Elementary analysis:

Cld: C 30.02 H 1.74 F 62.09

Fnd: C 29.87 H 1.95. F 61.81

b)10-[-2Hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

8.3 g (207.6 mmol) of sodium hydroxide is added to 12.0 g (34.60 mmol)of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml ofwater. A solution of 18.0 g (34.60 mmol) of the title compound ofExample 3a), dissolved in 60 ml of n-butanol/60 ml of 2-propanol, isadded dropwise to it, and the solution is heated overnight to 70° C. Itis evaporated to dryness in a vacuum, the residue is taken up in 300 mlof water and adjusted to pH 3 with 3N hydrochloric acid. Then, it isextracted twice with 200 ml of n-butanol. The combined butanol phasesare evaporated to dryness in a vacuum, and the residue is purified byRP-chromatography (RP-18/mobile solvent: gradient consisting ofwater/n-butanol/acetonitrile).

Yield: 26.61 g (79% of theory)

Water content: 11.0%

Elementary analysis (relative to anhydrous substance):

Cld: C 37.42 H 4.07 F 37.27 N 6.47

Fnd: C 37.25 H 4.19 F 37.08 N 6.30

c) Gadolinium complex of10-[-2hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (11.54 mmol) of the title compound of Example 3b) is dissolved in amixture of 100 ml of water/50 ml of 2-propanol, and 2.09 g (5.77 mmol)of gadolinium oxide is added. It is stirred for 3 hours at 80° C. Thesolution is filtered and evaporated to dryness in a vacuum.

Yield: 12.48 g (quantitative) of a vitreous solid

Water content: 5.6%

T₁-relaxivity (L/mmol·sec) at 20 MHz, 37° C.:

15.2 (water)

27.5 (human plasma)

Elementary analysis (relative to anhydrous substance):

Cld: C 31.77 H 3.16 F 31.64 Gd 15.40 N 5.49

Fnd: C 31.55 H 3.30 F 31.49 Gd 15.28 N 5.35

EXAMPLE 4 a)1,2-Epoxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorododecane

10.17 g (109.9 mmol) of epichlorohydrin is added in drops to a mixtureof 20 g (54.93 mmol) of 1H,1H,2H,2H-perfluorooctan-1-ol and 1.87 g (5.5mmol) of tetrabutylammonium hydrogen sulfate in 200 ml of 60% aqueouspotassium hydroxide solution/100 ml of toluene while being stirredvigorously at 10° C., and care is taken to ensure that the temperatureof the reaction solution is not higher than 20° C. It is allowed to stirfor 2 hours at 15° C., and then 5.08 g (54.93 mmol) of epichlorohydrinis added in drops as described above. Then, it is stirred overnight atroom temperature. 100 ml of toluene and 100 ml of methyl-tert-butylether are added, and the aqueous phase is separated. The latter isextracted twice more with 50 ml of toluene each. The organic phases arecombined, dried on magnesium sulfate and concentrated by evaporation ina vacuum. The residue is chromatographed on silica gel (mobile solvent:dichloromethane/hexane/acetone=20/10/1).

Yield: 19.15 g (83% of theory) of a colorless oil

Elementary analysis:

Cld: C 31.44 H 2.16 F 58.78

Fnd: C 31.40 H 2.29 F 58.55

b)10-[2-Hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorododecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10.3 g (257 mmol) of sodium hydroxide is added to 14.84 g (42.84 mmol)of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A) in 70ml of water. A solution of 18 g (42.84 mmol) of the title compound ofExample 4a), dissolved in 80 ml of n-butanol/60 ml of 2-propanol, isadded dropwise to it, and the solution is heated overnight to 70° C. Itis evaporated to dryness in a vacuum, the residue is taken up in 300 mlof water and adjusted to pH 3 with 3N hydrochloric acid. Then, it isextracted twice with 200 ml of n-butanol. The combined butanol phasesare evaporated to dryness in a vacuum, and the residue is purified byRP-chromatography (RP-18/mobile solvent: gradient consisting ofwater/n-butanol/acetonitrile).

Yield: 27.4 g (75% of theory) of a vitreous solid

Water content: 10.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 39.17 H 4.60 F 32.22 N 7.31

Fnd: C 39.05 H 4.85 F 32.05 N 7.19

c) Gadolinium complex of10-[2-hydroxy-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorododecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (13.04 mmol) of the title compound of Example 4b) is dissolved in amixture of 100 ml of water/50 ml of 2-propanol, and 2.36 g (6.52 mmol)of gadolinium oxide is added. It is stirred for 3 hours at 80° C. Thesolution is filtered and evaporated to dryness in a vacuum.

Yield: 12.77 g (quantitative) of a vitreous solid

Water content: 6.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 32.61 H 3.50 F 26.82 Gd 17.08 N 6.08

Fnd: C 32.43 H 3.69 F 26.67 Gd 16.85 N 5.91

EXAMPLE 5 a) 9,9,9,8,8,7,7,6,6-Nonafluoro-3-oxa-nonanoic acid-t-butylester

29.54 g (151.5 mmol) of bromoacetic acid-tert-butyl ester is added indrops to a mixture of 20 g (75.73 mmol) of1H,1H,2H,2H-perfluorohexan-1-ol and 2.57 g (7.57 mmol) oftetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassiumhydroxide solution/200 ml of toluene while being stirred vigorously at0° C. It is stirred for 1 hour at 0° C. 100 ml of toluene is added, theaqueous phase is separated and extracted twice with 50 ml of toluene.The combined organic phases are dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel (mobile solvent: hexane/dichloromethane/acetone=20/10/1).

Yield: 21.48 g (75% of theory) of a colorless oil

Elementary analysis:

Cld: C 38.11 H 4.00 F 45.21

Fnd: C 37.95 H 4.18 F 45.03

b) 9,9,9,8,8,7,7,6,6-Nonanefluoro-3-oxa-nonanoic acid

20 g (52.88 mmol) of the title compound of Example 5a) is dissolved in300 ml of trifluoroacetic acid and stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from hexane/ether.

Yield: 14.82 g (87% of theory) of a colorless crystalline solid

Elementary analysis:

Cld: C 29.83 H 2.19 F 53.08

Fnd: C 29.71 H 2.40 F 52.90

c) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,13-nonafluoro-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.41 g (23.01 mmol) of the title compound of Example 5b) and 2.91 g(25.31 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 40 mlof dimethylformamide/20 ml of chloroform. At 0° C., 5.22 g (25.31 mmol)of dicyclohexylcarbodiimide is added and stirred for 1 hour at 0° C.,then for 3 hours at room temperature. It is cooled again to 0° C., and6.98 g (69 mmol) of triethylamine/30 ml of 2-propanol is added. Then,13.2 g (23.01 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclodododecane,dissolved in 40 ml of water, is added and stirred for 3 hours at roomtemperature. It is evaporated to dryness, the residue is taken up in amixture of 200 ml of methanol/50 ml of chloroform, and dicyclohexylureais filtered out. The filtrate is evaporated to dryness and purified byRP-chromatography (RP-18/mobile solvent: gradient consisting ofwater/n-propanol/acetonitrile).

Yield: 15.20 g (71 of theory) of a colorless vitreous solid

Water content: 5.7%

Elementary analysis (relative to anhydrous substance):

Cld: C 34.21 H 4.02 F 19.48 Gd 17.91 N 7.98

Fnd: C 34.09 H 4.18 F 19.31 Gd 17.74 N 7.87

EXAMPLE 6 a) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-aceticacid-N-(2-aminoethyl)-amide

15 g (25.63 mmol) of the title compound of Example 1b) and 3.24 g (28.19mmol) of N-hydroxysuccinimide are dissolved in 80 ml ofdimethylformamide, and 5.82 g (28.19 mmol) of dicyclohexylcarbodiimideis added at 0° C. It is stirred for 1 hour at 0° C., then for 2 hours atroom temperature. Precipitated dicyclohexylurea is filtered out, and thefiltrate is added in drops within 30 minutes in a solution of 46.21 g(768.9 mmol) of ethylenediamine in 300 ml of dichloromethane. It isstirred for 5 hours at room temperature. 1000 ml of H₂O is added, andthe organic phase is separated. The latter is washed twice with 500 mlof water each, then dried on magnesium sulfate and evaporated to drynessin a vacuum. The purification is carried out by chromatography on silicagel. (Mobile solvent: dichloromethane/2-propanol=15/1).

Yield: 11.79 g (75% of theory) of a colorless, waxy solid

Elementary analysis:

Cld: C 27.42 H 2.30 F 52.66 N 4.57 S 5.23

Fnd: C 27.20 H 2.41 F 52.48 N 4.38 S 5.10

b) N-Ethyl-N-(perfluorooctylsulfonyl)-amino-aceticacid-N-[2-(bromoacetyl)-aminoethyl]-amide

10 g (16.3 mmol) of the title compound of Example 6a) and 2.02 g (20mmol) of triethylamine are dissolved in 40 ml of dichloromethane. At−10° C., 3.29 g (16.3 mmol) of bromoacetyl bromide is added in dropswithin 30 minutes and stirred for 2 hours at 0° C. The solution ispoured into 300 ml of 1N hydrochloric acid and stirred well. The organicphase is separated, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed on silica gel(mobile solvent: dichlormethane/acetone=20/1).

Yield: 11.1 g (91% of theory) of a slightly yellow-colored waxy solid

Elementary analysis:

Cld: C 25.68 H 2.02 Br 10.68 F 43.16 N 5.62 S 4.29

Fnd: C 25.47 H 2.18 Br 10.45 F 43.29 N 5.47 S 4.10

c)10-[2-Oxo-3-aza-6-aza-7-oxo-9-aza-9-(perfluorooctylsulfonyl)-undecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.63 g (13.36 mmol) of1,4,7-tris(carboxymethyl-1,4,7,10-tetraazacyclododecane (D03A) and 18.5g (133.6 mmol) of potassium carbonate are added to 10 g (13.36 mmol) ofthe title compound of Example 6b) in 180 ml of methanol. It is refluxedfor 12 hours. The inorganic salts are filtered off, and the filtrate isevaporated to dryness. The residue is taken up in 100 ml of water andadjusted to pH 3 with 5N hydrochloric acid. It is extracted twice with150 ml of n-butanol. The combined organic phases are evaporated todryness in a vacuum, and the residue is purified by RP-chromatography(RP-18/mobile solvent=gradient consisting ofwater/n-butanol/acetonitrile).

Yield: 10.43 g (67% of theory) of a colorless solid

Water content: 13.0%

Elementary analysis (relative to anhydrous substance):

Cld: C 35.55 H 3.98 F 31.86 N 9.67 S 3.16

Fnd: C 35.37 H 3.75 F 31.64 N 9.78 S 3.25

d) Gadolinium complex of10-[2-oxo-3-aza-6-aza-7-oxo-9-aza-9-(perfluorooctylsulfonyl)-undecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (9.86 mmol) of the title compound of Example 6c) is dissolved in amixture of 50 ml of water/20 ml of ethanol, and 1.79 g (4.93 mmol) ofgadolinium oxide is added. It is stirred for 4 hours at 80° C. Thesolution is filtered and evaporated to dryness in a vacuum.

Yield: 12.4 g (quantitative)

Water content: 7.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 30.85 H 3.19 F 27.65 Gd 13.46 N 8.39 S 2.75

Fnd: C 30.64 H 3.35 F 27.58 Gd 13.29 N 8.28 S 2.65

EXAMPLE 7 a) 1H,1H,2H,2H-Perfluorodecan-1-ol-p-toluenesulfonic acidester

12.57 g (65.93 mmol) of p-toluenesulfonic acid chloride is added to 30 g(64.64 mmol) of 1H,1H,2H,2H-perfluorodecan-1-ol in 300 ml ofdichloromethane and 10.12 g (100 mmol) of triethylamine at 0° C. It isstirred for 2 hours at 0° C., then for 2 hours at room temperature. Thesolution is poured into 500 ml of cold 2N hydrochloric acid and stirredvigorously. The organic phase is separated, dried on magnesium sulfateand evaporated to dryness. The residue is recrystallized from a littlemethanol.

Yield: 39.97 (95% of theory) of a colorless crystalline powder

Elementary analysis:

Cld: C 33.02 H 1.79 F 52.23 S 5.19

Fnd: C 32.81 H 1.93 F 52.04 S 5.05

b)10-[(1-Hydroxymethyl-1-carboxy)-methyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

37.2 g (173.4 mmol) of 2-chloro-3-benzyloxy-propanoic acid is added to asolution of 20 g (57.78 mmol) of1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (D03A), 31.21 g(780 mmol) of sodium hydroxide and 2 g (12 mmol) of potassium iodide in100 ml of dimethylformamide, and it is stirred for 3 days at 60° C. Itis evaporated to dryness, and the residue is dissolved in 300 ml ofwater. Then, it is adjusted to pH 3 with 3N hydrochloric acid andextracted twice with 250 ml of dichloromethane each. 4 g of palladiumcatalyst (10% Pd/C) is added to the aqueous phase and hydrogenated for 5hours at 60° C. The catalyst is filtered off, and the filtrate isevaporated to dryness. The residue is purified by RP-chromatography(RP-18/mobile solvent=gradient consisting ofwater/2-propanol/acetonitrile).

Yield: 5.92 g (21% of theory relative to D03A) of a colorless, vitreoussolid

Water content: 11.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 47.00 H 6.96 N 12.90

Fnd: C 46.81 H 6.78 N 12.99

c)10-[1-Hydroxymethyl-1-(methoxycarbonyl)-methyl]-1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

9.53 g (80 mmol) of thionyl chloride is added in drops to 200 ml ofmethanol at 0° C. Then, 5.8 g (13.35 mmol) of the title compound ofExample 7b) is added and stirred for 1 hour at 0° C. Then, it is heatedfor 6 hours to 60° C. It is evaporated to dryness, the residue is takenup in 150 ml of methylene chloride and extracted 3 times with 200 ml of8% aqueous soda solution each. The organic phase is dried on magnesiumsulfate and evaporated to dryness. 6.09 g (93% of theory) of the titlecompound is obtained as slightly yellowish-colored oil.

Elementary analysis:

Cld: C 51.42 H 7.81 N 11.42

Fnd: C 51.20 H 7.95 N 11.28

d)10-[1-(Methoxycarbonyl)-3-oxa-1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl]-1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

0.44 g (14.68 mmol) of sodium hydride (80% suspension in mineral oil) isadded to 6 g (12.23 mmol) of the title compound of Example 7c) in 40 mlof dimethylformamide and stirred for 30 minutes at −10° C. Then, 8.32 g(13.45 mmol) of the title compound of Example 7a) is added and stirredfor 8 hours at room temperature. 400 ml of ice water is carefully addedand extracted twice with 300 ml of ethyl acetate each. The combinedethyl acetate phases are washed with saturated aqueous common saltsolution and dried on magnesium sulfate. It is evaporated to dryness ina vacuum, and the residue is chromatographed on silica gel (mobilesolvent: dichloromethane/methanol=20/1).

Yield: 7.68 g (67% of theory) of a viscous yellow oil

Elementary analysis:

Cld: C 39.75 H 4.41 F 34.48 N 5.98

Fnd: C 39.58 H 4.60 F 34.27 N 5.75

e)10-[1-Carboxy-3-oxa-1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.5 g (8.01 mmol) of the title compound of Example 7d) is suspended in amixture of 50 ml of water/30 ml of ethanol, and then 3.84 g (96 mmol) ofsodium hydroxide is added. It is refluxed overnight. It is cooled toroom temperature and adjusted to pH 3 with 3N hydrochloric acid. It isevaporated to dryness in a vacuum, and the residue is purified byRP-chromatography (RP-18/mobile-solvent=gradient consisting ofwater/n-butanol/acetonitrile).

Yield: 6.84 g (87% of theory) of a vitreous solid

Water content: 10.3%

Elementary analysis (relative to anhydrous substance):

Cld: C 36.83 H 3.78 F 36.68 N 6.36

Fnd: C 36.67 H 3.90 F 36.49 N 6.25

f) Gadolinium complex of10-[1-carboxy-3-oxa-1H,2H,2H,4H,4H,5H,5H-perfluorotridecyl]1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(as sodium salt)

6 g (6.81 mmol) of the title compound of Example 7e) is suspended in 80ml of water, and 1.23 g (3.4 mmol) of gadolinium oxide is added. It isheated for 3 hours to 90° C. It is allowed to cool to room temperatureand adjusted to pH 7.2 with 2N sodium hydroxide solution. The solutionis filtered and then freeze-dried.

Yield: 7.83 g (quantitative) of a colorless, flocculent powder

Water content: 8.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 30.69 H 2.77 F 30.56 Gd 14.88 N 5.30 Na 2.18

Fnd: C 30.48 H 2.85 F 30.37 Gd 14.69 N 5.17 Na 1.95

EXAMPLE 8 a) 2H,2H-Perfluorooctanal

30 g (82.4 mmol) of 1H,1H,2H,2H-perfluorooctan-1-ol is dissolved in 500ml of dichloromethane, and 17.76 g (82.4 mmol) of pyridiniumchlorochromate is added. It is stirred overnight at room temperature.The solution is filtered with a short column, filled with aluminum oxide(neutral), the filtrate is evaporated to dryness and the residue ischromatographed on silica gel (mobile solvent:dichloromethane/hexane/acetone=10/10/1).

Yield: 26.55 g (89% of theory) of a waxy solid

Elementary analysis:

Cld: C 26.54 H 0.84 F 68.21

Fnd: C 26.47 H 1.05 F 68.10

b) 2-Amino-2H,3H,3H-perfluorononanoic acid (as hydrochloride)

7.04 g (143.6 mmol) of sodium cyanide and 8.45 g (158 mmol) of ammoniumchloride are dissolved in 30 ml of water. 40 ml of ethanol and 26 g(71.8 mmol) of the title compound of Example 8a) are added to thissolution. It is heated for 2 hours to 45° C. 300 ml of water is added,and it is extracted 3 times with 200 ml of benzene each. The combinedbenzene phases are washed 3 times with 200 ml of water each, and theorganic phase is evaporated to dryness in a vacuum. The residue is takenup in 100 ml of 6N aqueous hydrochloric acid/50 ml of methanol andrefluxed for 2 hours. It is evaporated to dryness in a vacuum. Theresidue is recrystallized from a little 2-propanol/methyl-tert-butylether.

Yield: 11.15 g (35% of theory) of a crystalline solid

Elementary analysis:

Cld: C 24.37 H 1.59 Cl 7.99 F 55.68 N 3.16

Fnd: C 24.15 H 1.72 Cl 7.65 F 55.51 N 3.05

c)2-[(N-Benzyloxycarbonyl)-triglycidyl]-amino-2H,3H,3H-perfluorononanoicacid

8.37 g (24.8 mmol) of N-benzyloxycarbonyl-triglycine and 3.14 g (27.28mmol) of N-hydroxysuccinimide are dissolved in 80 ml ofdimethylformamide, and 5.63 g (27.28 mmol) of dicyclohexylcarbodiimideis added at 0° C. It is stirred for 1 hour at 0° C., then for 2 hours atroom temperature. It is cooled to 0° C., 7.53 g (74.4 mmol) oftriethylamine and 11 g (24.8 mmol) of the title compound of Example 8bare added and then stirred overnight at room temperature. It isevaporated to dryness in a vacuum, the residue is taken up in 300 ml of5% aqueous citric acid and extracted 3 times with 200 ml of ethylacetate each. The combined organic phases are dried on magnesium sulfateand evaporated to dryness in a vacuum. The residue is chromatographed onsilica gel (mobile solvent: dichloromethane/n-propanol=20/1).

Yield: 11.83 g (67% of theory) of a colorless, sheetlike solid

Elementary analysis:

Cld: C 38.78 H 2.97 F 34.67 N 7.86

Fnd: C 38.59 H 2.85 F 34.48 N 7.91

d) 2-[Triglycidyl]-amino-2H,3H,3H-perfluorononanoic acid

11.5 g (16.14 mmol) of the title compound of Example 8c) is dissolved in200 ml of 2-propanol, and 3 g of palladium catalyst (10% Pd/C) is added.It is hydrogenated overnight at room temperature. Catalyst is filteredout, and the filtrate is evaporated to dryness.

Yield: 9.33 g (quantitative) of a colorless solid

Elementary analysis:

Cld: C 31.15 H 2.61 F 42.71 N 9.69

Fnd: C 31.29 H 2.80 F 42.53 N 9.48

e)2-(1H,1H-Perfluoroheptyl)-1,4,7,10-tetraaza-3,6,9,12-tetraoxo-cyclododecane

9.2 g (15.91 mmol) of the title compound of Example 8d) is dissolved in1000 ml of dimethylformamide, and 3.93 g (15.91 mmol) of2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline is added. It is stirredfor 3 days at room temperature. It is evaporated to dryness, and theresidue is chromatographed on silica gel (mobile solvent:dichloromethane/2-propanol=20/1).

Yield: 4.54 g (51% of theory) of a waxy solid

Elementary analysis:

Cld: C 32.16 H 2.34 F 44.08 N 10.00

Fnd: C 32.05 H 2.47 F 43.87 N 9.89

f) 2-(1H,1H-Perfluoroheptyl)-1,4,7,10-tetraazacyclododecane (astetrahydrochloride)

200 ml of 1M borane-tetrahydrofuran complex solution is added to 4.4 g(7.85 mmol) of the title compound of Example 8e) and refluxed for 2days. It is evaporated to dryness in a vacuum, and the residue is takenup in 50 ml of concentrated hydrochloric acid. 100 ml of ethanol isadded, and it is refluxed for 8 hours. It is evaporated to dryness in avacuum, and the residue is recrystallized from ethanol.

Yield: 4.75 g (93% of theory) of a colorless, crystalline powder

Elementary analysis:

Cld: C 27.71 H 3.88 Cl 21.81 F 37.99 N 8.62

Fnd: C 27.65 H 3.95 Cl 21.40 F 37.69 N 8.41

g)2-(1H,1H-Perfluoroheptyl)-1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.6 g (7.07 mmol) of the title compound of Example 8f) and 4.0 g (42.4mmol) of chloroacetic acid are dissolved in 40 ml of water, and the pHis adjusted to 10 by adding 30% aqueous potassium hydroxide solution. Itis heated for 8 hours to 70° C. and in this case, the pH is kept between8 and 10 (by adding 30% aqueous potassium hydroxide solution). Thesolution is cooled to room temperature, adjusted to pH 2 withconcentrated hydrochloric acid and evaporated to dryness. The residue istaken up in 150 ml of methanol, the salts are filtered off and thefiltrate is evaporated to dryness in a vacuum. The residue is purifiedby RP-18 chromatography (RP-18/mobile solvent: gradient consisting ofwater/2-propanol/acetonitrile).

Yield: 5.03 g (87% of theory) of a vitreous solid

Water content: 10.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 37.51 H 3.97 F 33.53 N 7.61

Fnd: C 37.35 H 4.12 F 33.40 N 7.45

h) Gadolinium complex of2-(1H,1H-perfluoroheptyl)-1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane(as sodium salt)

4.5 g (6.11 mmol) of the title compound of Example 8g) is suspended in100 ml of water, and 1.107 g (3.05 mmol) of gadolinium oxide is added.It is heated for 3 hours to 90° C. It is allowed to cool to roomtemperature and adjusted to pH 7.2 with 2N sodium hydroxide solution.The solution is filtered and then freeze-dried.

Yield: 6.03 g (quantitative) of a colorless powder

Water content: 7.5%

Elementary analysis (relative to anhydrous substance):

Cld: C 30.23 H 2.87 F 27.03 Gd 17.21 N 6.13 Na 2.52

Fnd: C 30.10 H 3.05 F 26.81 Gd 17.15 N 5.95 Na 2.30

EXAMPLE 9 a)10-[2-Hydroxy-1H,1H,2H,3H,3H-perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

13.85 g (346.4 mmol) of sodium hydroxide is added to 15 g (43.3 mmol) of1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml ofwater. A solution of 27.68 g (64.95 mmol) of1,2-epoxy-1H,1H,2H,3H,3H-perfluorononane, dissolved in 50 ml ofn-butanol/50 ml of 2-propanol, is added dropwise to it, and the solutionis heated overnight to 80° C. It is evaporated to dryness in a vacuum,the residue is taken up in 200 ml of water and adjusted to pH 3 with 3Nhydrochloric acid. Then, it is extracted twice with 200 ml of n-butanol.The combined butanol phases are evaporated to dryness in a vacuum, andthe residue is purified by RP-chromatography (RP-18/mobile solvent:gradient consisting of water/n-butanol/acetonitrile).

Yield: 30.34 g (78% of theory) of a vitreous solid

Water content: 13.7%

Elementary analysis (relative to anhydrous substance):

Cld: C 37.32 H 4.04 F 36.89 N 7.25

Fnd: C 37.15 H 4.21 F 36.70 N 7.19

b) Gadolinium complex of10-[2-hydroxy-1H,1H,2H,3H,3H-perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (12.94 mmol) of the title compound of Example 9a) is dissolved in100 ml of water/50 ml of ethanol, and 2.34 g (6.47 mmol) of gadoliniumoxide is added. It is stirred for 3 hours at 80° C. The solution isfiltered and evaporated to dryness in a vacuum.

Yield: 13.16 g (quantitative) of a colorless, vitreous solid

Water content: 9.1%

Elementary analysis (relative to anhydrous substance):

Cld: C 31.11 H 3.05 F 30.75 Gd 16.97 N 6.05

Fnd: C 31.01 H 3.19 F 30.55 Gd 16.71 N 5.88

EXAMPLE 10 a) 9H,9H,10H,11H,12H,12H-Perfluoroeicos-10-ene

24.77 g (52.26 mmol) of 1H,1H,2H,2H-perfluorodecyl-1-iodide and 13.71 g(52.26 mmol) of triphenylphosphine are heated to 70° C. in 500 ml ofacetone while being stirred. The initially clear solution quickly turnsmilky, and the colorless phosphonium salt is precipitated. Thephosphonium salt is filtered off and dried in a vacuum at 40° C.

Yield: 38.9 g (89% of theory)

This phosphonium salt is used directly in the following reaction withoutpurification: 5.22 g (46.5 mmol) of potassium-tert-butylate, 0.20 g(0.75 mmol) of 18-crown 6 and 19.54 g (42.28 mmol) of2H,2H-perfluorodecanol are added to the above-produced phosphonium salt,38.9 g (46.5 mmol) in 250 ml of dichloromethane, and it is stirred for10 hours at room temperature. It is evaporated to dryness, and theresidue is chromatographed on silica gel (mobile solvent:dichloromethane/n-hexane/diethyl ether=10/20/1).

Yield: 30.3 g (65% of theory relative to the iodide used) of a colorlesswaxy solid

Elementary analysis:

Cld: C 26.92 H 0.68 F 72.40

Fnd: C 26.81 H 0.79 F 72.20

b) 10,11-Epoxy-9H,9H,10H,11H,12H,12H-perfluoroeicosane

10.47 g (36.42 mmol) of 3-chloroperoxybenzoic acid (about 60%) is addedto 25 g (28.02 mmol) of the title compound of Example 10a), dissolved in250 ml of dichloromethane, at 0° C., and it is stirred overnight at roomtemperature. 300 ml of 5% aqueous sodium carbonate solution is added andstirred well. The organic phase is separated, dried on magnesium sulfateand evaporated to dryness in a vacuum. The residue is chromatographed onsilica gel (mobile solvent: n-hexane/dichloromethane/diethylether=10/10/1).

Yield: 24.17 g (95% of theory) of a colorless solid

Elementary analysis:

Cld: C 26.45 H 0.67 F 71.12

Fnd: C 26.25 H 0.88 F 71.35

c)10-[1-(1H,1H-Perfluorononyl)-2-hydroxy-1H,2H,3H,3H-perfluoroundecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.04 g (0.176 mmol) of sodium hydroxide is added to 7.63 g (22.02 mmol)of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 35 ml ofwater. A solution of 20 g (22.02 mmol) of the title compound of Example10b), dissolved in 50 ml of n-butanol/40 ml of 2-propanol, is addeddropwise to it, and the solution is heated overnight to 120° C. in anautoclave. It is evaporated to dryness in a vacuum, the residue is takenup in 200 ml of water and adjusted to pH 3 with 3N hydrochloric acid.Then, it is extracted twice with 300 ml of n-butanol. The combinedbutanol phases are evaporated to dryness in a vacuum, and the residue ispurified by RP-chromatography (RP-18/mobile solvent: gradient consistingof water/n-butanol/acetonitrile).

Yield: 9.79 g (31% of theory) of a colorless, vitreous solid

Water content: 12.5%

Elementary analysis (relative to anhydrous substance):

Cld: C 32.55 H 2.57 F 51.49 N 4.47

Fnd: C 32.38 H 2.75 F 51.29 N 4.28

d) Gadolinium complex of10-[1-(1H,1H-perfluorononyl)-2-hydroxy-1H,2H,3H,3H-perfluoroundecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

8 g (6.38 mmol) of the title compound of Example 10c) is dissolved in 50ml of water/40 ml of ethanol/20 ml of chloroform, and 1.16 g (3.19 mmol)of gadolinium oxide is added. It is stirred for 4 hours at 90° C. in anautoclave. The solution is filtered and evaporated to dryness in avacuum.

Yield: 9.47 g (quantitative) of a vitreous solid

Water content: 5.2%

Elementary analysis (relative to anhydrous substance):

Cld: C 28.99 H 2.07 F 45.85 Gd 11.16 N 3.98

Fnd: C 28.81 H 2.19 F 45.71 Gd 11.03 N 4.12

EXAMPLE 11 a) 7H,7H,8H,9H,10H,10H-Perfluorohexadec-8-ene

18.7 g (50 mmol) of 1H,1H,2H,2H-perfluorooctyl-1-iodide and 13.11 g (50mmol) of triphenylphosphine are heated to 70° C. in 400 ml of acetonewhile being stirred. The initially clear solution quickly turns milky,and the colorless phosphonium salt is precipitated. The phosphonium saltis filtered off and dried in a vacuum at 40° C.

Yield: 28.95 g (91% of theory)

This phosphonium salt is used directly in the following reaction withoutpurification: 5.05 g (45.5 mmol) of potassium-tert-butylate, 0.20 g(0.75 mmol) of 18-crown 6 and 14.98 g (41.36 mmol) of the title compoundof Example 8a) are added to the above-produced phosphonium salt, 28.95 g(45.5 mmol) in 200 ml of dichloromethane, and it is stirred for 10 hoursat room temperature. It is evaporated to dryness, and the residue ischromatographed on silica gel (mobile solvent:dichloromethane/n-hexane/diethyl ether=10/20/1).

Yield: 19.65 g (61% of theory) of a colorless, waxy solid

Elementary analysis:

Cld: C 22.38 H 0.94 F 76.69

Fnd: C 22.20 H 0.99 F 76.51

b) 8,9-Epoxy-7H,7H,8H,9H,10H,10H-perfluorohexadecane

11.03 g (38.35 mmol) of 3-chloroperoxybenzoic acid (about 60%) is addedto 19 g (29.5 mmol) of the title compound of Example 11a), dissolved in200 ml of dichloromethane, at 0° C., and it is stirred overnight at roomtemperature. 300 ml of 5% aqueous sodium carbonate solution is added andstirred well. The organic phase is separated, dried on magnesium sulfateand evaporated to dryness in a vacuum. The residue is chromatographed onsilica gel (mobile solvent: n-hexane/dichloromethane/diethylether=10/10/1).

Yield: 19.43 g (93% of theory) of a colorless solid

Elementary analysis:

Cld: C 27.14 H 0.85 F 69.75

Fnd: C 27.01 H 0.97 F 69.60

c)10-[1-(1H,1H-Perfluoroheptyl)-2-hydroxy-1H,2H,3H,3H-perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

8.59 g (214.6 mmol) of sodium hydroxide is added to 9.3 g (26.83 mmol)of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 50 ml ofwater. A solution of 19 g (26.83 mmol) of the title compound of Example11b), dissolved in 70 ml of n-butanol/60 ml of 2-propanol, is addeddropwise to it, and the solution is heated overnight to 120° C. in anautoclave. It is evaporated to dryness in a vacuum, the residue is takenup in 200 ml of water and adjusted to pH 3 with 3N hydrochloric acid.:Then, it is extracted twice with 300 ml of n-butanol. The combinedbutanol phases are evaporated to dryness in a vacuum, and the residue ispurified by RP-chromatography (RP-18/mobile solvent: gradient consistingof water/n-butanol/acetonitrile).

Yield: 9.4 g (29% of theory) of a vitreous solid

Water content: 12.7%

Elementary analysis (relative to anhydrous substance):

Cld: C 34.17 H 3.06 F 46.84 N 5.31

Fnd: C 33.98 H 3.18 F 46.65 N 5.20

d) Gadolinium complex of10-[1-(1H,1H-perfluoroheptyl)-2-hydroxy-1H,2H,3H,3H-perfluorononyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

9 g (8.53 mmol) of the title compound of Example 11c) is dissolved in 60ml of water/40 ml of ethanol/30 ml of chloroform, and 1.54 g (4.27 mmol)of gadolinium oxide is added. It is stirred for 4 hours at 90° C. in anautoclave. The solution is filtered and evaporated to dryness in avacuum.

Yield: 11.45 g (quantitative) of a colorless, vitreous solid

Water content: 10.2%

Elementary analysis (relative to anhydrous substance):

Cld: C 29.81 H 2.42 F 40.86 Gd 13.01 N 4.63

Fnd: C 29.60 H 2.60 F 40.63 Gd 12.84 N 4.51

EXAMPLE 12 a)7,12-Dioxa-5H,5H,6H,6H,8H,8H,9H,10H,11H,11H,13H,13H,14H,14H-perfluorooctadec-9-ene

30 g (91.74 mmol) of 1H,1H,2H,2H-perfluorohexyl-1-bromide is dissolvedin 100 ml of toluene, then 3.23 g (36.7 mmol) of cis-1,4-butene-diol and1 g (2.95 mmol) of tetrabutylammonium hydrogen sulfate are added. It iscooled to 0° C., and 16 g (400 mmol) of finely powdered sodium hydroxideis added. Then, it is stirred for 1 hour at 0° C. and overnight at roomtemperature. Solid is filtered out, the filtrate is washed twice with200 ml of water each, the organic phase is dried on magnesium sulfateand then evaporated to dryness in a vacuum. The residue ischromatographed on silica gel (mobile solvent:dichloromethane/n-hexane/acetone=15/15/1).

Yield: 11.71 g (55% of theory relative to diol) of a waxy solid

Elementary analysis:

Cld: C 33.12 H 2.43 F 58.93

Fnd: C 33.05 H 2.61 F 58.73

b)9,10-Epoxy-7,12-dioxa-5H,5H,6H,6H,8H,8H,9H,10H,11H,11H,13H,13H,14H,14H-perfluorooctadecane

7.08 g (24.64 mmol) of 3-chloroperoxybenzoic acid (about 60%) is addedto 11 g (18.96 mmol) of the title compound of Example 12a), dissolved in100 ml of dichloromethane, at 0° C., and it is stirred overnight at roomtemperature. 150 ml of 5% aqueous sodium carbonate solution is added andstirred well. The organic phase is separated, dried on magnesium sulfateand evaporated to dryness in a vacuum. The residue is chromatographed onsilica gel (mobile solvent: n-hexane/dichloromethane/diethylether=10/10/1).

Yield: 10.74 g (95% of theory) of a colorless solid

Elementary analysis:

Cld: C 32.23 H 2.37 F 57.35

Fnd: C 32.13 H 2.51 F 57.20

c)10-[1-(2-Oxa-1H,1H,3H,3H,4H,4H-perfluorooctyl)-2-hydroxy-4-oxa-1H,2H,3H,3H,5H,5H,6H,6H-perfluorodecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

5.63 g (141 mmol) of sodium hydroxide is added to 6.1 g (17.61 mmol) of1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 40 ml ofwater. A solution of 10.5 g (17.61 mmol) of the title compound ofExample 12b), dissolved in 50 ml of n-butanol/40 ml of 2-propanol, isadded dropwise to it, and the solution is heated overnight to 120° C. inan autoclave. It is evaporated to dryness in a vacuum, the residue istaken up in 200 ml of water and adjusted to pH 3 with 3N hydrochloricacid. Then, it is extracted twice with 300 ml of n-butanol. The combinedbutanol phases are evaporated to dryness in a vacuum, and the residue ispurified by RP-chromatography (RP-18/mobile solvent: gradient consistingof water/n-butanol/acetonitrile).

Yield: 4.96 g (27% of theory) of a colorless, vitreous solid

Water content: 9.7%

Elementary analysis (relative to anhydrous substance): Cld: C, 38.27; H,4.17; F, 36.32; N, 5.95. Fnd: C, 38.12; H, 4.20; F, 36.20; N, 5.81.

d) Gadolinium complex of10-[1-(2-oxa-1H,1H,3H,3H,4H,4H-perfluorooctyl)-2-hydroxy-4-oxa-1H,2H,3H,3H,5H,5H,6H,6H-perfluorodecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.7 g (5 mmol) of the title compound of Example 12c) is dissolved in 30ml of water/30 ml of ethanol/20 ml of chloroform, and 0.90 g (2.5 mmol)of gadolinium oxide is added. It is stirred for 3.5 hours at 90° C. inan autoclave. The solution is filtered and evaporated to dryness in avacuum.

Yield: 5.89 g (quantitative) of a colorless, vitreous solid

Water content: 7.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 32.88; H,3.31; F, 31.21; Gd, 14.35; N, 5.11. Fnd: C, 32.67; H, 3.45; F, 31.04;Gd, 14.18; N, 5.02.

EXAMPLE 13 a)1-Phenyl-2,6-dioxa-1H,1H,3H,3H,4H,5H,5H,7H,7H,8H,8H-perfluorohexa-decan-4-ol

1 g (2.94 mmol) of tetrabutylammonium hydrogen sulfate and 15.6 g (390mmol) of finely powdered sodium hydroxide are added to 7.14 g (39.2mmol) of glycerol-1-monobenzylether and 25 g (43.55 mmol) of1H,1H,2H,2H-perfluorodecyl-1-iodide in 100 ml of toluene. It is stirredfor 24 hours at room temperature. The organic phase is separated fromthe solid and washed twice with 5% aqueous hydrochloric acid each. Theorganic phase is dried on magnesium sulfate and evaporated to dryness ina vacuum. The residue is chromatographed on silica gel (mobile solvent:n-hexane/acetone=15/1).

Yield: 19.95 g (81% of theory) of a colorless oil

Elementary analysis: Cld: C, 38.23; H, 2.73; F, 51.40. Fnd: C, 38.10; H,2.89; F, 51.25.

b)1-Phenyl-4-(decyloxy)-2,6-dioxa-1H,1H,3H,3H,4H,5H,5H,7H,7H,8H,8H-perfluorohexadecane

1.12 g (37.24 mmol) of sodium hydride (80% suspension in mineral oil) isadded in portions to 19.5 g (31.03 mmol) of the title compound ofExample 13a), dissolved in 100 ml of dimethylformamide, and it isstirred for 2 hours at room temperature. Then, 8.24 g (37.24 mmol) ofn-decyl bromide is added and stirred overnight at 50° C. 150 ml of icewater is added and extracted twice with 150 ml of ethyl acetate each.The combined organic phases are washed twice with 150 ml of water each,dried on magnesium sulfate and evaporated to dryness. The residue ischromatographed on silica gel (mobile solvent: n-hexane/acetone=20:1);

Yield: 22.66 g (95% of theory) of a waxy solid

Elementary analysis: Cld: C, 46.88; H, 4.85; F, 42.02. Fnd: C, 46.64; H,4.97; F, 41.87.

c)2-(Decyloxy)-4-oxa-1H,1H,2H,3H,3H,5H,5H,6H,6H-perfluorotetradecan-1-ol

20 g (26.02 mmol) of the title compound of Example 13b) is dissolved in200 ml of isopropanol, and 3 g of palladium catalyst (10% Pd/C) isadded. It is hydrogenated overnight at room temperature. The catalyst isfiltered off, and the filtrate is evaporated to dryness in a vacuum.

Yield: 17.65 g (quantitative) of a colorless solid

Elementary analysis: Cld: C, 40.72; H, 4.61; F, 47.60. Fnd: C, 40.55; H,4.76; F, 47.43.

d)1,2-Epoxy-4-oxa-6-(decyloxy)-8-oxa-1H,1H,2H,3H,3H,5H,5H,6H,7H,7H,9H,9H,10H,10H-perfluorooctadecane

9.25 g (100 mmol) of epichlorohydrin is added in drops to a mixture of17 g (25.06 mmol) of the title compound of Example 13c) and 2 g (5.89mmol) of tetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueouspotassium hydroxide solution/100 ml of toluene while being stirredvigorously at 10° C., and care is taken to ensure that the temperatureof the reaction solution does not exceed 20° C. It is allowed to stirfor 2 hours at 15° C., and then 4.63 g (50 mmol) of epichlorohydrin isadded in drops as described above. Then, it is stirred overnight at roomtemperature. 100 ml of toluene and methyl-tert-butyl ether are added,and the aqueous phase is separated. The latter is extracted twice morewith 100 ml of toluene each. The organic phases are combined, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:dichloromethane/hexane/acetone=20/10/1).

Yield: 14.91 g (81% of theory) of a colorless solid

Elementary analysis: Cld: C, 42.51; H, 4.80; F, 43.97. Fnd: C, 42.37; H,4.96; F, 43.68.

e)10-[2-Hydroxy-4,8-dioxa-6-(decyloxy)-1H,1H,2H,3H,3H,5H,5H,6H,7H,7H,9H,9H,10H,10H-perfluorooctadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

6.11 g (152.8 mmol) of sodium hydroxide is added to 6.6 g (19.06 mmol)of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 60 ml ofwater. A solution of 14 g (19.06 mmol) of the title compound of Example13d), dissolved in 80 ml of n-butanol/40 ml of 2-propanol, is addeddropwise to it, and the solution is heated overnight to 80° C. in anautoclave. It is evaporated to dryness in a vacuum, the residue is takenup in 200 ml of water, and it is adjusted to pH 3 with 3N hydrochloricacid. Then, it is extracted twice with 300 ml of n-butanol. The combinedbutanol phases are evaporated to dryness in a vacuum, and the residue ispurified by RP-chromatography (RP-18/mobile solvent: gradient consistingof water/n-butanol/acetonitrile).

Yield: 17.88 g (76% of theory) of a vitreous solid

Water content: 12.5%

Elementary analysis (relative to anhydrous substance): Cld: C, 44.49; H,5.60; F, 29.91; N, 5.19. Fnd: C, 44.31; H, 5.75; F, 29.70; N, 5.03.

f) Gadolinium complex of10-[2-hydroxy-4,8-dioxa-6-(decyloxy)-1H,1H,2H,3H,3H,5H,5H,6H,7H,7H,9H,9H,10H,10H-perfluorooctadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (9.26 mmol) of the title compound of Example 13e) is dissolved in30 ml of water/100 ml of ethanol/30 ml of chloroform, and 1.68 g (4.63mmol) of gadolinium oxide is added. It is stirred for 3.5 hours at 90°C. in an autoclave. The solution is filtered and evaporated to drynessin a vacuum.

Yield: 12.39 g (quantitative) of a colorless, vitreous solid

Water content: 7.8%

Elementary analysis (relative to anhydrous substance): Cld: C, 38.93; H,4.66; F, 26.17; Gd, 12.74; N, 4.54. Fnd: C, 38.71; H, 4.82; F, 26.01;Gd, 12.55; N, 4.38.

EXAMPLE 14 a)1-Phenyl-2-oxa-4,4,4-tris(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-butane

2 g (5.89 mmol) of tetrabutylammonium hydrogen sulfate and 22.48 g (562mmol) of finely powdered sodium hydroxide are added to 4.24 g (18.74mmol) of pentaerythritol monobenzyl ether and 40 g (93.7 mmol) of1H,1H,2H,2H-perfluorooctyl-1-bromide in 150 ml of toluene. It is stirredfor 24 hours at room temperature. The organic phase is separated fromthe solid and washed twice with 5% aqueous hydrochloric acid each. Theorganic phase is dried on magnesium sulfate and evaporated to dryness ina vacuum. The residue is chromatographed on silica gel (mobile solvent:n-hexane/acetone=25/1).

Yield: 14.45 g (61% of theory relative to the benzyl ether) of acolorless, waxy solid

Elementary analysis: Cld: C, 34.19; H, 2.15; F, 58.59. Fnd: C, 34.02; H,2.31; F, 58.41.

b) 2,2,2-Tris(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-ethan-1-ol

14 g (11.07 mmol) of the title compound of Example 14a) is dissolved in100 ml of isopropanol/100 ml of tetrahydrofuran, and 3 g of palladiumcatalyst (10% Pd/C) is added. It is hydrogenated overnight at roomtemperature. The catalyst is filtered off, and the filtrate isevaporated to dryness in a vacuum.

Yield: 13 g (quantitative) of a colorless solid

Elementary analysis: Cld: C, 29.66; H, 1.80; F, 63.09. Fnd: C, 29.45; H,1.97; F, 62.91.

c)1,2-Epoxy-4-oxa-6,6,6-tris(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-hexane

3.94 g (42.57 mmol) of epichlorohydrin is added in drops to a mixture of12.5 g (10.64 mmol) of the title compound of Example 14b) and 1 g (2.95mmol) of tetrabutylammonium hydrogen sulfate in 150 ml of 60% aqueouspotassium hydroxide solutibn/50 ml of toluene while being stirredvigorously at 10° C., and care is taken to ensure that the temperatureof the reaction solution does not exceed 20° C. It is allowed to stirfor 2 hours at 15° C., and then 1.97 g (21.29 mmol) of epichlorohydrinis added in drops as described above. Then, it is stirred overnight atroom temperature. 100 ml of toluene and 100 ml of methyl-tert-butylether are added, and the aqueous phase is separated. The latter isextracted twice more with 50 ml of toluene each. The organic phases arecombined, dried on magnesium sulfate and concentrated by evaporation ina vacuum. The residue is chromatographed on silica gel (mobile solvent:dichloromethane/hexane/acetone=20/10/1).

Yield: 8.12 g (62% of theory) of a colorless solid

Elementary analysis: Cld: C, 31.24; H, 2.05; F, 60.22. Fnd: C, 31.09; H,2.19; F, 60.10.

d)10-[2-Hydroxy-4-oxa-6,6,6-tris(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-hexyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

2.08 g (52 mmol) of sodium hydroxide is added to 2.25 g (6.50 mmol) of1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in 30 ml ofwater. A solution of 8.0 g (6.50 mmol) of the title compound of Example14c), dissolved in 50 ml of n-butanol/30 ml of 2-propanol, is addeddropwise to it, and the solution is heated overnight to 100° C. in anautoclave. It is evaporated to dryness in a vacuum, the residue is takenup in 200 ml of water and adjusted to pH 3 with 3N hydrochloric acid.Then, it is extracted twice with 100 ml of n-butanol. The combinedbutanol phases are evaporated to dryness in a vacuum, and the residue ispurified by RP-chromatography (RP-18/mobile solvent: gradient consistingof water/n-butanol/acetonitrile).

Yield: 7.79 g (67% of theory) of a colorless, vitreous solid

Water content: 11.9%

Elementary analysis (relative to anhydrous substance): Cld: C, 35.06; H,3.20; F, 47.02; N, 3.56. Fnd: C, 34.90; H, 3.38; F, 46.86; N, 3.47.

e) Gadolinium complex of10-[2-hydroxy-4-oxa-6,6,6-tris(2-oxa-1H,1H,3H,3H,4H,4H-perfluorodecyl)-hexyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7 g (4.44 mmol) of the title compound of Example 14d) is dissolved in 30ml of water/50 ml of ethanol/50 ml of chloroform, and 0.80 g (2.22 mmol)of gadolinium oxide is added. It is stirred for 5 hours at 90° C. in anautoclave. The solution is filtered and evaporated to dryness in avacuum.

Yield: 8.34 g (quantitative) of a colorless, vitreous solid

Water content: 8.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 31.94; H,2.74; F, 42.83; Gd, 9.09; N, 3.24. Fnd: C, 31.74; H, 2.91; F, 42.67; Gd,8.85; N, 3.15.

EXAMPLE 15 a)1,7-Bis[acetyl-(2-(N-ethyl-N-perfluorooctylsulfonylamino)]-1,4,7-triazaheptane

20 g (34.17 mmol) of the title compound of Example 1b) and 4.33 g (37.59mmol) of N-hydroxysuccinimide are dissolved in 150 ml ofdimethylformamide. 7.76 g (37.59 mmol) of dicyclohexylcarbodiimide isadded at 0° C. and stirred for 3 hours at room temperature.Dicyclohexylurea is filtered out, and the filtrate is added in drops toa solution of 1.76 g (17.09 mmol) of diethylenetriamine and 13.83 g(136.7 mmol) of triethylamine in 200 ml of dimethylformamide at roomtemperature. It is stirred overnight at room temperature. It isevaporated to dryness in a vacuum, and the residue is taken up in 200 mlof 5% aqueous soda solution. It is extracted twice with 150 ml ofdichloromethane each, the combined organic phases are dried on magnesiumsulfate and evaporated to dryness in a vacuum. The residue ischromatographed on silica gel (mobile solvent:dichloromethane/2-propanol=20/1).

Yield: 16.5 g (78% of theory) of a waxy solid

Elementary analysis: Cld: C, 27.17; H, 2.04; F, 52.19; N, 5.66; S, 5.18.Fnd: C, 27.03; H, 2.17; F, 52.04; N, 5.49; S, 5.07.

b)4-(3-Carboxy-propanoyl)-1,7-bis-{acetyl-[2-(N-ethyl-N-perfluorooctylsulfonylamino)]}-1,4,7-triazaheptane

3.92 g (38.78 mmol) of triethylamine is added to 16 g (12.93 mmol) ofthe title compound of Example 15a) in 100 ml of methylene chloride, andthe solution is cooled to 0° C. Then, 2.59 g (25.86 mmol) of succinicanhydride is added and stirred for 3 hours at 0° C., overnight at roomtemperature. 200 ml of 5% aqueous hydrochloric acid is added and shakenwell. The organic phase is separated and dried on magnesium sulfate. Itis evaporated to dryness in a vacuum, and the residue is chromatographedon silica gel (mobile solvent: dichloromethane/2-propanol=15/1).

Yield: 15.74 g (91% of theory) of a colorless solid

Elementary analysis: Cld: C, 28.73; H, 2.19; F, 48.29; N, 5.24; S, 4.79.Fnd: C, 28.58; H, 2.40; F, 48.17; N, 5.17; S, 4.65.

c) 10-(7-Hydroxy-5-aza-4-oxo-octanoicacid-N,N-bis(3-aza-4-oxo-6-aza-6-(perfluorooctylsulfonyl)-octyl)-amide]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

15 g (11.21 mmol) of the title compound of Example 15b) and 1.42 g(12.33 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 80 mlof dimethylformamide/30 ml of chloroform. 2.54 g (12.33 mmol) ofdicyclohexylcarbodiimide is added at 0° C. and stirred for 1 hour at 0°C., then for 3 hours at room temperature. It is cooled again to 0° C.,and 4.05 g (40 mol) of triethylamine/50 ml of 2-propanol is added. Then,7.07 g (12.33 mmol) of the gadolinium complex of10-[2-hydroxy-3-amino-propyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane,dissolved in 30 ml of water, is added and stirred for 3 hours at roomtemperature. It is evaporated to dryness, the residue is taken up in amixture of 100 ml of methanol/50 ml of chloroform, and dicyclohexylureais filtered out. The filtrate is evaporated to dryness and purified byRP-chromatography (RP-18/mobile solvent: gradient consisting ofwater/n-propanol/acetonitrile).

Yield: 17.76 g (78% of theory) of a colorless, vitreous solid

Water content: 6.8%

Elementary analysis (relative to anhydrous substance): Cld: C, 31.08; H,3.03; F, 34.12; Gd, 8.31; N, 7.40; S, 3.39. Fnd: C, 30.89; H, 3.15; F,34.01; Gd, 8.14; N, 7.25; S, 3.24.

EXAMPLE 16 Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-tetraazacyclododecanea)16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-Heptadecafluoro-3,6,9,12-tetra-oxa-docosan-1-ol

A mixture of 20 g (32.35 mmol) of1-p-toluenesulfonyloxy-1H,1H,2H,2H-perfluorodecane [see Example 7a], 1 gof tetrabutylammonium hydrogen sulfate, 62.83 g (323.5 mmol) oftetraethylene glycol, 300 ml of dichloromethane and 100 ml of 50% sodiumhydroxide solution is stirred intensively at about 5° C. for 24 hours.It is then diluted with 200 ml of dichloromethane, the phases areseparated, and the dichloromethane phase is washed with water. Theorganic phase is dried on magnesium sulfate and concentrated byevaporation in a vacuum. 18.5 g of the desired title compound isobtained as light yellow oil.

b)1,2-Epoxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane

A mixture of 17 g (26.5 mmol) of16,16,17,17,18,18,19,19,20,20,21,21,22,22,22-heptadecafluoro-3,6,9,12-tetra-oxa-docosan-1-ol,0.5 g of tetrabutylammonium hydrogen sulfate, 2.94 g of epichlorohydrin,200 ml of dichloromethane and 50 ml of 50% sodium hydroxide solution isstirred intensively at room temperature for 8 hours. The phases areseparated, the aqueous phase is shaken with 100 ml of dichloromethane,the organic phases are combined, shaken with 50 ml of water, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Theresidue is chromatographed on silica gel with hexane/5-50% ethylacetate, and 12.92 g of the title compound is obtained as oil.

Elementary analysis: Cld: C, 36.22; H, 3.62; F, 46.38. Fnd: C, 36.00; H,3.78; F, 46.20.

c)1,4,7-Tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-tetraazacyclododecane

A solution of 12.05 g (17.3 mmol) of1,2-epoxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosanein 50 ml of tetrahydrofuran is added to a solution of 6 g (17.3 mmol) of1,4,7-(triscarboxylatomethyl)-1,4,7,10-tetraazacyclododecane and 4 g ofsodium hydroxide in 30 ml of water. It is stirred overnight at 70° C.,then largely concentrated by evaporation in a vacuum, the residue istaken up in 150 ml of water and adjusted to pH 3 with 6N hydrochloricacid and extracted several times with n-butanol. The combined extractsare concentrated by evaporation in a vacuum, and the residue is purifiedby chromatography on RP-18 with a gradient consisting ofwater/n-butanol/acetonitrile. 13.71 g of the title compound is obtainedas yellow viscous oil.

Elementary analysis: Cld: C, 40.31; H, 4.93; F, 30.97; N, 5.37. Fnd: C,40.08; H, 5.21; F, 30.77; N, 5.29.

d) Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-tetraazacyclododecane

A mixture of 5 g (4.79 mmol) of1,4,7-tris(carboxylatomethyl)-10-(2-hydroxy-19,19,20,20,21,21,22,22,23,23,24,24,25,25,26,26,26-heptadecafluoro-4,7,10,13,16-penta-oxa-hexacosane)-1,4,7,10-tetraazacyclododecane,50 ml of water and 30 ml of ethanol is mixed with 869 mg (2.397 mmol) ofgadolinium oxide, and it is refluxed for 5 hours. The hot solution isfiltered and concentrated by evaporation in a vacuum. 5.60 g of thetitle compound is obtained as a vitreous, solid substance with a watercontent of 4.1%.

Elementary analysis (relative to anhydrous substance): Cld: C, 35.12; H,4.04; F, 26.98; Gd, 13.14; N, 4.68. Fnd: C, 34.90; H, 4.38; F, 26.70;Gd, 13.10; N, 4.62.

EXAMPLE 17 Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-(4-aza-2-hydroxy-26,26,26,25,25,24,24,23,23,22,22,21,21,20,20,19,19-heptadecafluoro-5-oxo-16-thia-hexacosyl)-1,4,7,10-tetraazacyclododecanea)22,22,22,21,21,20,20,19,19,18,18,17,17,16,16,15,15-Heptadecafluoro-12-thia-docosanoicacid

A solution of 10 g (37.71 mmol) of 11-bromoundecanoic acid in 150 ml ofdichloromethane is mixed with 11.43 g of triethylamine and 18.11 g(37.71 mmol) of 1H,1H,2H,2H-perfluorodecylmercaptan, and it is stirredovernight at room temperature. The solution is extracted several timeswith 2N hydrochloric acid, washed with common salt solution, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. 21.5 g ofthe title compound is obtained as yellow oil.

Elementary analysis: Cld: C, 37.96; H, 3.79; F, 48.61; S, 4.83. Fnd: C,38.30; H, 4.01; F, 48.40; S, 5.20.

b) Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-(4-aza-2-hydroxy-26,26,26,25,25,24,24,23,23,22,22,21,21,20,20,19,19-heptadecafluoro-5-oxo-16-thia-hexacosyl)-1,4,7,10-tetraazacyclododecane

5 g (7.52 mmol) of the title compound of Example 17a) and 0.95 g ofN-hydroxysuccinimide are dissolved in a mixture of 25 ml ofdimethylformamide and 15 ml of chloroform. 1.71 g ofdicyclohexylcarbodiimide is added at 0° C. and stirred for 1 hour at 0°C., then for 3 hours at room temperature. It is then cooled again to 0°C. and mixed with 3 ml of triethylamine and 20 ml of n-propanol. Then,4.75 g (8.27 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane,dissolved in 25 ml of water, is added and stirred for 3 hours at 20° C.It is evaporated to dryness, the residue is taken up in a mixture of 55ml of methanol and 20 ml of chloroform, and dicyclohexylurea is filteredout. The filtrate is evaporated to dryness and purified bychromatography on RP-18 with a gradient consisting ofwater/n-propanol/acetonitrile. 6.15 g of the title compound is obtainedas a vitreous solid, with a water content of 2.3%.

Elementary analysis (relative to anhydrous substance): Cld: C, 37.41; H,4.38; F, 26.47; Gd, 12.89; N, 5.74; S, 2.63. Fnd: C, 37.08; H, 4.60; F,26.30; Gd, 12.68; N, 5.91; S, 2.49.

EXAMPLE 18 Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-[1-(1,2-dihydroxyethyl)3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-tetraazacyclododecanea) 1-p-Toluenesulfonyloxy-1H,1H,2H,2H-perfluorooctane

20 ml of pyridine is added to a solution of 25 g (68.7 mmol) of1H,1H,2H,2H-perfluorooctan-1-ol in 300 ml of dichloromethane at 0° C.,and 13.49 g (70.76 mmol) of p-toluenesulfonic acid chloride is added inportions while being stirred. It is stirred for 3 more hours at 0° C.,and the dichloromethane is drawn off at room temperature in a vacuum.The remaining pyridine solution is mixed with ice water, whereby thedesired product precipitates. The residue is decanted and dissolved indichloromethane, the solution is washed with water, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. The residue ispurified by chromatography on silica gel with hexane/5-40% ethylacetate. 29.2 g of the title compound is obtained as viscous foam.

Elementary analysis: Cld: C, 34.76; H, 2.14; F, 47.65; S, 6.19. Fnd: C,34.98; H, 2.38; F, 47.39; S, 6.42.

b)1,4,7-Tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-undecane-1,4,7,10-tetraazacyclododecane

20 ml of 50% sodium hydroxide solution, 0.5 g of tetrabutylammoniumhydrogen sulfate and 5.18 g (10 mmol) of1-p-toluenesulfonyloxy-1H,1H,2H,2H-perfluorooctane [see Example 18a)]are added in succession to 7.33 g (10 mmol) of1,4,7-tris(benzyloxycarbonyl)-10-[2-hydroxy-1-(2,2-dimethyl-1,3-dioxolan-4-yl]-ethyl-1,4,7,10-tetraazacyclododecane[J. Mag. Res. Imag. 5, 7-10, (1955)], dissolved in 100 ml ofdichloromethane, and the mixture is stirred intensively overnight atroom temperature. The phases are separated, the organic phase is washedseveral times with water, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The residue is purified by chromatography onsilica gel with dichloromethane/1-10% ethanol. 8.02 g of the titlecompound is obtained as viscous oil.

Elementary analysis: Cld: C, 53.01; H, 5.02; F, 23.19; N, 5.26. Fnd: C,53.30; H, 5.39; F, 23.01; N, 5.40.

c)1-[1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-undecane-1,4,7,10-tetraazacyclododecane

A solution of 7 g (6.57 mmol) of1,4,7-tris(benzyloxycarbonyl)-10-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-undecane-1,4,7,10-tetraazacyclododecanein 100 ml of isopropyl alcohol is mixed with 0.7 g of palladium oncarbon (10%), and it is shaken for 3 hours under hydrogen atmosphere.Catalyst is filtered out, and the solution is concentrated byevaporation in a vacuum. 4.20 g of the title compound is obtained asvitreous foam.

Elementary analysis: Cld: C, 41.70; H, 5.32; F, 37.28; N, 8.46. Fnd: C,41.61; H, 5.57; F, 37.10; N, 8.59.

d)1,4,7-Tris(carboxylatomethyl)-10-[1-(1,2-dihydroxy-ethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-tetraazacyclododecane

3.36 g (24.15 mmol) of bromoacetic acid in 50 ml of water is dissolvedand mixed with 6N sodium hydroxide solution until pH 7 is reached. Asolution of 4 g (6.04 mmol) of1-[1-(2,2-dimethyl-1,3-dioxolan-4-yl)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-3-oxa]-undecane-1,4,7,10-tetraazacyclododecane,dissolved in 20 ml of isopropyl alcohol, and enough 6N sodium hydroxidesolution are added in drops at 40° C. while simultaneously being stirredso that the pH is kept at 9-10. Then, it is mixed with semiconcentratedhydrochloric acid up to pH 1 and stirred for another 3 hours at 60° C.It is cooled to room temperature, and the solution is extracted severaltimes with n-butanol. The organic extract is concentrated byevaporation, and the residue is purified by chromatography on RP-18 witha gradient consisting of water/n-butanol/acetonitrile. 3.85 g of thetitle compound is obtained as yellow oil with a water content of 3.9%.

Elementary analysis (relative to anhydrous substance): Cld: C, 39.20; H,4.68; F, 31.00; N, 7.03. Fnd: C, 39.08; H, 4.98; F, 30.72; N, 7.29.

e) Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-[1-(1,2-dihydroxy-ethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-tetraazacyclododecane

A mixture of 1.59 g (2 mmol) of1,4,7-tris(carboxylatomethyl)-10-[1-(1,2-dihydroxy-ethyl)-3-oxa-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro]undecane-1,4,7,10-tetraazacyclododecane,25 ml of water and 15 ml of ethanol is mixed with 363 mg (1 mmol) ofgadolinium oxide, and it is refluxed for 5 hours. The hot solution isfiltered, concentrated by evaporation in a vacuum, and 1.85 g of thetitle compound is obtained as a vitreous, solid substance with a watercontent of 4.2%.

Elementary analysis (relative to anhydrous substance): Cld: C, 32.84; H,3.60; F, 25.98; Gd, 16.54; N, 5.89. Fnd: C, 32.53; H, 3.71; F, 25.72;Gd, 16.39; N, 5.93.

EXAMPLE 19 Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecanea) 1-Hydroxy-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzene

5 g (45.41 mmol) of hydroquinone is mixed with 100 ml of acetone andmixed while being stirred in succession with 13.8 g of potassiumcarbonate and 14.04 g (22.7 mmol) of1-p-toluenesulfonyloxy-1H,1H,2H,2H-perfluorodecane [see Example 7a)]. Itis refluxed for 6 hours, then largely concentrated by evaporation in avacuum, diluted with 200 ml of water, adjusted to pH 3 with citric acidand extracted several times with dichloromethane. The organic extract isdried on magnesium sulfate and concentrated by evaporation in a vacuum.The residue is purified by chromatography on silica gel withhexane/5-30% ethyl acetate. 8.20 g of the desired title compound isobtained as viscous oil.

Elementary analysis: Cld: C, 34.55; H, 1.63; F, 58.07. Fnd: C, 34.31; H,1.79; F, 58.01.

b)1-(3,4-Epoxy-1-oxa-but-1-yl)-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzene

A mixture of 8 g (14.38 mmol) of1-hydroxy-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzene, 0.4 g oftetrabutylammonium hydrogen sulfate, 1.60 g (17.26 mmol) ofepichlorohydrin, 150 ml of dichloromethane and 30 ml of 50% sodiumhydroxide solution is stirred intensively for 30 minutes in an ice bath,then for 5 hours at room temperature. The phases are separated, theorganic phase is washed with water, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is purified bychromatography on silica gel with hexane/5-30% ethyl acetate, and 6.60 gof the title compound is obtained as viscous oil.

Elementary analysis: Cld: C, 37.27; H, 2.41; F, 52.75. Fnd: C, 37.10; H,2.66; F, 52.80.

c)1,4,7-Tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-(4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane

A solution of 6.12 g (10 mmol) of1-(3,4-epoxy-1-oxa-but-1-yl)-4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)-benzenein 25 ml of tetrahydrofuran is added to a solution of 3.46 g (10 mmol)of 1,4,7-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane and 2.5g of sodium hydroxide in 25 ml of water, and it is refluxed for 24hours, then largely concentrated by evaporation in a vacuum, the residueis dissolved in 100 ml of water, adjusted to pH 3 with 6N hydrochloricacid and extracted several times with n-butanol. The combined extractsare concentrated by evaporation in a vacuum. The residue is purified bychromatography on RP-18 with a gradient consisting ofwater/n-butanol/acetonitrile. 6.71 g of the title compound is obtainedas viscous oil.

Elementary analysis: Cld: C, 41.35; H, 4.10; F, 33.69; N, 5.84. Fnd: C,41.58; H, 4.38; F, 33.50; N, 5.91.

d) Gadolinium complex of1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane

A mixture of 4.79 g (5 mmol) of1,4,7-tris(carboxylatomethyl)-10-{2-hydroxy-4-oxa-4-[4-(2H,2H,3H,3H-1-oxa-perfluoroundec-1-yl)]-phenyl}-but-1-yl-1,4,7,10-tetraazacyclododecane,50 ml of water and 30 ml of ethanol is mixed with 906 mg (2.5 mmol) ofgadolinium oxide and refluxed for 5 hours. The hot solution is filteredand concentrated by evaporation in a vacuum. 5.50 g of the titlecompound is obtained as a vitreous solid substance with a water contentof 4.9%.

Elementary analysis (relative to anhydrous substance): Cld: C, 35.62; H,3.26; F, 29.02; Gd, 14.13; N, 5.03. Fnd: C, 35.40; H, 3.50; F, 28.81;Gd, 14.01; N, 5.18.

EXAMPLE 20 Gadolinium complex, disodium salt of3,9-bis(carboxymethyl)-6-[(1-carboxy)-1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-3,6,9-triazaundecanedioicacid a)N-t-Butoxycarbonyl-serine-(1H,1H,2H,2H-perfluorodecyl)-ether-benzylester

300 mg (10 mmol) of sodium hydride (80% in oil) is added in portions toa solution of 2.953 g (10 mmol) of N-t-butyloxycarbonyl-serine-benzylester (Bachem commercially available products) in 30 ml of drydimethylformamide. After dissolving is completed, it is mixed with 6.072g (10 mmol) of the tosylate produced under 7a). It is stirred for 12hours at room temperature. Then, it is poured into 500 ml of ice water,the product is taken up in dichloromethane, the organic solution iswashed with water, dried on sodium sulfate and evaporated to dryness.The residue is purified by chromatography on silica gel. A mixture ofdichloromethane with increasing addition of methanol is used as eluant.

The title compound is obtained as syrup.

Yield: 5.902 g (79.6% of theory)

Elementary analysis: Cld: C, 40.50; H, 3.26; F, 43.56; N, 1.89. Fnd: C,40.64; H, 3.37; F, 43.49; N, 1.83.

b) Serine-(1H,1H,2H,2H-perfluorodecyl)-ether-benzyl ester (as salt oftrifluoroacetic acid

7.414 g (10 mmol) of the N-protected compound that is produced under20a) is dissolved in 50 ml of a mixture of trifluoroacetic acid anddichloromethane at a 2:1 ratio, and it is stirred overnight at roomtemperature. It is evaporated to dryness, and the remainder of thetrifluoroacetic acid is removed by codistillation with ethanol. Thetitle compound is isolated as a salt of trifluoroacetic acid.

Yield: 7.418 g (98.2% of theory)

Elementary analysis: Cld: C, 34.98; H, 2.27; F, 50.30; N, 1.85. Fnd: C,34.89; H, 2.31; F, 50.39; N, 1.80.

c)3,9-Bis(t-butoxycarbonylmethyl)-6-[(1-benzyloxycarbonyl)-1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl)-3,6,9-triazaundecanedioicacid-di(t-butyl)-ester

3.777 g (5 mmol) of the amine-trifluoroacetate that is produced under20b) and 3.523 g (10 mmol) ofN,N-bis(t-butyloxycarbonylmethyl)-2-(bromoethyl)-amine are added to amixture of 10 ml of acetonitrile and 20 ml of phosphate buffer of pH8.0, and it is stirred intensively at room temperature for 2 hours.Then, the buffer phase is separated, extracted with 10 ml ofacetonitrile, and the latter is added to the organic phase. After 20 mlof fresh buffer is added, it is stirred for 20 more hours at roomtemperature. The organic phase is separated, concentrated byevaporation, and the residue is dispersed between 100 ml of phosphatebuffer (pH 8.0) and 100 ml of ethyl acetate. The organic phase is washedwith saturated common salt solution, dried on sodium sulfate andconcentrated by evaporation. The title compound is purified bychromatography on silica gel. Dichloromethane is used as eluant withincreasing addition of methanol. The title compound is obtained as aglass-like solid.

Yield: 3.162 g (53.4% of theory)

Elementary analysis: Cld: C, 48.69; H, 5.62; F, 27.28; N, 3.55. Fnd: C,48.82; H, 5.72; F, 27.37; N, 3.50.

d)3,9-Bis(carboxymethyl)-6-[(1-carboxy)-1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-3,6,9-triazaundecanedioicacid

5.920 g (5 mmol) of the compound that is produced under 20c) is added toa mixture of 25 ml of trifluoroacetic acid/dichloromethane at a 2:1ratio. It is allowed to stir overnight at room temperature, thenevaporated to dryness, the residue is taken up in 100 ml of 3Nhydrochloric acid, refluxed for 3 hours, then evaporated to dryness in avacuum and taken up in 160 ml of a mixture of water, ethanol andchloroform (10:5:1). The solution is set at a constant pH (about 3) byadding ion exchanger IRA 67 (OH⁻ form). It is quickly suctioned off, andthe title compound is obtained as a vitreous solid.

Yield: 3.080 g (71.3% of theory)

Water content: 11.3%

Elementary analysis (relative to anhydrous substance): Cld: C, 34.53; H,3.25; F, 37.15; N, 4.83. Fnd: C, 34.41; H, 3.32; F, 37.29; N, 4.90.

e) Gadolinium complex, disodium salt of3,9-bis(carboxymethyl)-6-[(1-carboxy)-1H,2H,2H,4H,4H,5H,5H-3-oxa-perfluorotridecyl]-3,6,9-triazaundecanedioicacid

2.941 g (3.0 mmol, relative to 11.3% water content) of the acid that isproduced under 20d) is added to a mixture of 60 ml of distilled waterand 30 ml of ethanol. 543.8 mg (1.5 mmol) of gadolinium oxide is addedin portions while being stirred and heated to 50° C. After addition iscompleted, it is stirred until dissolved. The pH of the solution is thenadjusted to 7.2 by adding sodium hydroxide solution. The solution isthen concentrated by evaporation, whereby strong foaming can beobserved. The residue is codistilled with distilled water. The titlecompound is obtained as a vitreous solid.

Yield: 3.489 g (quantitative)

Water content: 8.2%

Elementary analysis (relative to anhydrous substance): Cld: C, 28.12; H,2.17; F, 30.25; Gd, 14.73; N, 3.94; Na, 4.31. Fnd: C, 28.25; H, 2.26; F,30.40; Gd, 14.85; N, 3.99; Na, 4.38.

EXAMPLE 21 Gadolinium complex, monosodium salt of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-mono-N-{ethyl-2-amino-[carbonylmethyl-amino-(N-ethyl-N-perfluorooctylsulfonyl)]}-amidea) 3,6,9-Tris(carboxylatomethyl)-3,6,9-triazaundecanedioicacid-mono-N-{ethyl-2-amino-[carbonylmethyl-amino-(N-ethyl-N-perfluorooctylsulfonyl)]}-amide

17.87 g (50 mmol) of diethylenetriaminepentaacetic acid-bis-anhydride issuspended in 200 ml of a mixture of dimethylformamide anddichloromethane at a 4:1 ratio and mixed in portions with the mixture of3.137 g (5 mmol) of[N-(2-aminoethyl)-N-perfluorooctylsulfonyl]-aminoaceticacid-N-(2-aminoethyl)-amide and 6.50 g (64.2 mmol) of triethylaminewhile being stirred vigorously. It is allowed to stir for 5 more hours,evaporated to dryness, mixed with 300 ml of ice water, and the pH of thebatch is adjusted to about 3 with 3N hydrochloric acid. It is extractedtwice with 200 ml of n-butanol each, the organic solutions are combinedand concentrated by evaporation. The product is purified bychromatography on silica gel RP-18. Water and tetrahydrofuran are usedas eluants. The title compound is obtained as a vitreous solid.

Yield: 2.722 g (54.3% of theory)

Water content: 9.7%

Elementary analysis (relative to anhydrous substance): Cld: C, 33.54; H,3.52; F, 32.21; N, 8.38; S, 3.20. Fnd: C, 33.65; H, 3.60; F, 32.14; N,8.51; S, 3.29.

b) Gadolinium complex, monosodium salt of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-mono-N-{ethyl-2-amino-[carbonylmethyl-amino-(N-ethyl-N-perfluorooctylsulfonyl)]}-amide

3.259 g (3 mmol, relative to 9.7% water) of the compound that isproduced under 21a) is added to 90 ml of a mixture of distilled waterand ethanol (2:1). While being stirred, 543.8 mg (1.5 mmol) ofgadolinium oxide is added in portions. It is stirred until dissolved,then the pH of the solution is adjusted to 7.2 by adding sodiumhydroxide solution, and it is concentrated by evaporation, wherebystrong foaming occurs. The residue is codistilled with distilled water.The title compound is obtained as a glass-like solid.

Yield: 3.861 g (quantitative)

Water content: 8.4%

The elementary analysis is relative to anhydrous substance: Cld: C,28.53; H, 2.65; F, 27.40; Gd, 13.34; N, 7.13; Na, 1.95; S, 2.72. Fnd: C,28.61; H, 2.68; F, 27.48; Gd, 13.40; N, 7.08; Na, 1.99; S, 2.76.

EXAMPLE 22 Gadolinium complex, monosodium salt of3,9-bis(carboxymethyl)-6-1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11H,11H-2,7-dioxo-3,6-diaza-9-oxa-perfluoromonodecyl)-3,6,9-triazaundecanedioicacid a) Glycolicacid-(1H,1H,2H,2H-perfluorodecyl)-ether-N-(2-aminoethyl)-amide

10.44 g (20 mmol) of compound 2b) is dissolved in 80 ml ofdichloromethane and mixed with 2.30 g (20 mmol) of N-hydroxysuccinimideas well as 4.13 g (20 mmol) of dicyclohexylcarbodiimide. It is allowedto stir overnight, dicyclohexylurea is filtered out, and the filtrate isstirred in a solution of 60.1 g (1000 mmol) of ethylenediamine in 100 mlof dichloromethane. It is allowed to stir overnight, mixed with 1.5 l ofwater, and the organic phase is separated. The dichloromethane solutionis washed with water, dried on sodium sulfate, evaporated to dryness andthe residue is purified by chromatography on silica gel. A mixture ofdichloromethane with increasing addition of isopropanol is used aseluant.

Yield: 9.615 g (85.2% of theory)

Elementary analysis: Cld: C, 29.80; H, 2.32; F, 57.24; N, 4.96. Fnd: C,29.96; H, 2.37; F, 57.12; N, 5.01.

b) Glycolicacid-(1H,1H,2H,2H-perfluorodecyl)-ether-N-[ethyl-2-(benzyloxycarbonyl-aminomethylcarbonylamino)]-amide

2.092 g (10 mmol) of benzyloxycarbonylglycine is dissolved in 15 ml ofdichloromethane and mixed with 1.151 g (10 mmol) of N-hydroxysuccinimideas well as 2.063 g (10 mmol) of dicyclohexylcarbodiimide. It is allowedto stir overnight, dicyclohexylurea is filtered out and evaporated todryness. The residue is purified on silica gel by column chromatography.A mixture of dichloromethane and ethanol is used as eluant. The titlecompound is obtained as a vitreous solid.

Yield: 6.905 g (91.40% of theory)

Elementary analysis: Cld: C, 38.16; H, 2.94; F, 42.75; N, 5.56. Fnd: C,38.28; H, 2.98; F, 42.82; N, 5.50.

c) Glycolicacid-(1H,1H,2H,2H-perfluorodecyl)-ether-N-[ethyl-(2-aminomethyl-carboxylamino)-amide

3.777 g (5 mmol) of the compound that is produced under 22b) ishydrogenated in 100 ml of a mixture of tetrahydrofuran and ethanol at a2:1 ratio in the presence of 0.2 g of Pearlman's catalyst (Pd 20%/C)until 112 ml of hydrogen is taken up. Catalyst is suctioned off,rewashed well with ethanol and evaporated to dryness. The title compoundis obtained as a glass-like solid.

Yield: 3.097 g (99.7% of theory)

Elementary analysis: Cld: C, 30.93; H, 2.60; F, 51.98; N, 6.76. Fnd: C,30.87; H, 2.64; F, 52.11; N, 6.82.

d)3,9-Bis(t-butyloxycarbonylmethyl)-6-(1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11H,11H,-2,7-dioxo-3,6-diaza-9-oxa-perfluorononadecyl)3,6,9-triazaundecanedioicacid-bis(t-butylester)

3.107 g (5 mmol) of the amine that is produced under 22c) and 3.523 g(10 mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-(bromoethyl)-amine areadded to a mixture of 10 ml of acetonitrile and 20 ml of phosphatebuffer of pH 8 and stirred intensively for 2 hours at room temperature.Then, the buffer phase is separated, it is extracted with 10 ml ofacetonitrile, and the latter is added to the organic phase. After 20 mlof fresh buffer is added, it is stirred for 20 more hours at roomtemperature. The organic phase is separated, it is concentrated byevaporation, and the residue is dispersed between 100 ml of phosphatebuffer (pH 8.0) and 100 ml of ethyl acetate. The organic phase is washedwith saturated common salt solution, dried on sodium sulfate andconcentrated by evaporation. The compound is purified on silica gel bychromatography. Dichloromethane with increasing addition of methanol isused as eluant. The title compound is obtained as a glass-like solid.

Yield: 3.044 g (52.3% of theory)

Elementary analysis: Cld: C, 45.40; H, 5.71; F, 27.75; N, 6.02. Fnd: C,45.47; H, 5.78; F, 27.68; N, 6.10.

e)3,9-Bis(carboxymethyl)-6-(1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11H,11H-2,7-dioxo-3,6-diaza-9-oxa-perfluoromonodecyl)-3,6,9-triazaundecanedioicacid

5.820 g (5 mmol) of the compound that is produced under 22d) is added toa mixture of 120 ml of trifluoroacetic acid/dichloromethane at a 2:1ratio. It is allowed to stir overnight at room temperature, evaporatedto dryness, the remainder of trifluoroacetic acid is removed bycodistillation with ethanol and taken up in 240 ml of a mixture ofwater, ethanol and chloroform. The solution is set at a constant pH(about 3) by adding ion exchanger IRA-67 (OH⁻ form). It is quicklysuctioned off, concentrated by evaporation, and the title compound isobtained as a vitreous solid.

Yield: 3.214 g (68.4% of theory)

Water content: 10.3%

Elementary analysis (relative to anhydrous substance): Cld: C, 35.79; H,3.65; F, 34.37; N, 7.45. Fnd: C, 35.90; H, 3.72; F, 34.31; N, 7.51.

f) Gadolinium complex, monosodium salt of3,9-bis(carboxymethyl)-6-(1H,1H,4H,4H,5H,5H,8H,8H,10H,10H,11H,11H-2,7-dioxo-3,6-diaza-9-oxa-perfluorononadecyl)-3,6,9-triazaundecanedioicacid

3.143 g (3.0 mmol, relative to 10.3% water content) of the acid that isproduced under 22e) is added to a mixture of 60 ml of distilled waterand 30 ml of ethanol. 543.8 mg (1.5 mmol) of gadolinium oxide is addedin portions while being stirred and heated to 50° C. After addition iscompleted, it is stirred until dissolved. Then, the pH of the solutionis adjusted to 7.2 by adding sodium hydroxide solution, the solution isconcentrated by evaporation, whereby strong foaming can be observed. Theresidue is codistilled with distilled water. The title compound isobtained as a vitreous solid.

Yield: 3.635 g (quantitative)

Water content: 7.9%

Elementary analysis (relative to anhydrous substance): Cld: C, 30.14; H,2.71; F, 28.95; Gd, 14.09; N, 6.28; Na, 2.06. Fnd: C, 30.21; H, 2.78; F,29.03; Gd, 14.16; N, 6.22; Na, 2.11.

EXAMPLE 23 Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-[2-aminoethyl-(N-ethyl-N-perfluorooctylsulfonyl]-amide} a)N-Ethyl-(2-benzyloxycarbonylamino-ethyl)-perfluorooctylsulfonic acidamide

5.272 g (10 mmol) of perfluorooctylsulfonic acid-N-ethylamide isdissolved in 30 ml of dimethylformamide. With exclusion of moisture, itis mixed with 330 mg (11 mmol) of sodium hydride (80% in oil). After gasgeneration is completed, the solution of 2.093 g (10 mmol) ofN-benzyloxycarbonyl-aziridine is added dropwise to it. It is poured into300 ml of ice water, extracted with dichloromethane, the organicsolution is washed with water, it is dried on sodium sulfate andevaporated to dryness. The residue is chromatographed on silica gel withdichloromethane/methanol. The title compound is a glass-like solid.

Yield: 6.149 g (87.3% of theory)

Elementary analysis: Cld: C, 34.10; H, 2.43; F, 45.85; N, 3.98; S, 4.55.Fnd: C, 34.00; H, 2.49; F, 45.97; N, 4.06; S, 4.49.

b) N-Ethyl-N-2-(aminoethyl)-perfluorooctylsulfonamide

3.522 g (5 mmol) of the compound that is produced under 23a) ishydrogenated in 100 ml of a mixture of tetrahydrofuran and ethanol at a2:1 ratio in the presence of 0.2 g of Pearlman's catalyst (Pd 20w/C)until 112 ml of hydrogen is taken up. Catalyst is suctioned off, it isrewashed well with ethanol and evaporated to dryness. The title compoundis obtained as an amorphous solid.

Yield: 2.814 g (98.7% of theory)

Elementary analysis: Cld: C, 25.27; H, 1.94; F, 56.64; N, 4.91; S, 5.62.Fnd: C, 25.39; H, 1.99; F, 56.57; N, 4.96; S, 5.53.

c) 3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-[2-aminoethyl-(N-ethyl-N-perfluorooctylsulfonyl)]-amide}

5.703 g (10 mmol) of the compound that is produced under 23b) as well as1.518 g (15 mmol) of triethylamine are dissolved in 30 ml of drydimethylformamide and mixed in portions with 1.787 g (5 mmol) ofdiethylenetriaminepentaacetic acid-bisanhydride while being stirred andwith exclusion of moisture. It is allowed to stir overnight, thenconcentrated by evaporation, mixed with water, the pH is adjusted toabout 3 with 3N hydrochloric acid, and it is extracted twice with 100 mlof n-butanol each. The organic solutions are combined, concentrated byevaporation and subjected to a chromatography on silica gel RP-18. Waterand -tetrahydrofuran are used as eluant. The title compound is obtainedas a glass-like solid.

Yield: 6.172 g (82.4% of theory)

Water content: 9.8%.

Elementary analysis (relative to anhydrous substance): Cld: C, 30.47; H,2.76; F, 43.12; N, 6.55; S, 4.28. Fnd: C, 30.59; H, 2.81; F, 43.00; N,6.61; S, 4.33.

d) Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-[2-aminoethyl-(N-ethyl-N-perfluorooctylsulfonyl)]-amide}

6.570 g (4 mmol, relative to 9.8% water content) of the compound that isproduced under 23c) is added to a mixture of 120 ml of distilled water,60 ml of ethanol and 20 ml of chloroform. 725 mg (82.0 mmol) ofgadolinium oxide is added in portions while being stirred and heated to50° C. It is stirred until dissolved, then concentrated by evaporation,whereby strong foaming occurs, and the residue is subjected tocodistillation with distilled water. The codistillation is repeatedtwice. The title compound is obtained as a glass-like solid.

Yield: 7.191 g (quantitative)

Water content: 8.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 27.63; H,2.32; F, 39.10; Gd, 9.52; N, 5.93; S, 3.88. Fnd: C, 27.50; H, 2.37; F,39.22; Gd, 9.61; N, 5.85; S, 3.95.

EXAMPLE 24 Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-<2-aminoethyl-[glycolicacid-(1H,1H,2H,2H-perfluorodecyl-ether)-amide]>-amide} a)3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-<2-aminoethyl-glycolicacid-(1H,1H,2H,2H-perfluorodecyl-ether)-amide]>-amide}

6.771 g (12 mmol) of the compound that is produced under Example 22a) aswell as 1.821 g (18 mmol) of triethylamine are dissolved in 40 ml of drydimethylformamide and mixed in portions with 2.144 g (6 mmol) ofdiethylenetriaminepentaacetic acid-bisanhydride while being stirred andwith exclusion of moisture. It is allowed to stir overnight, thenconcentrated by evaporation, mixed with 20 ml of water, the pH isadjusted to about 3, and it is extracted with 3N hydrochloric acid twicewith 150 ml of butanol each. The organic solutions are combined,concentrated by evaporation, and the residue is subjected to achromatography on silica gel RP-18. Water and tetrahydrofuran are usedas eluant. The title compound is obtained as a glass-like solid.

Yield: 6.989 g (78.4% of theory)

Water content: 7.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 33.95; H,3.05; F, 43.47; N, 6.60. Fnd: C, 34.06; H, 3.11; F, 43.40; N, 6.67.

b) Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis{N-<2-aminoethyl-[glycolicacid-(1H,1H,2H,2H-perfluorodecyl-ether) -amide]>-amide}

4.798 g (3 mmol, relative to 7.1% water) of the compound that isproduced under 24a) is added to a mixture of 100 ml of distilled water,50 ml of ethanol and 20 ml of chloroform. 543.8 mg (1.5 mmol) ofgadolinium oxide is added in portions while being stirred and heated to50° C. It is stirred until dissolved, then concentrated by evaporation,whereby strong foaming occurs. The residue is codistilled several timeswith distilled water. The title compound is obtained as a glass-likesolid.

Yield: 5.285 g (quantitative)

Water content: 6.9%

The elementary analysis is relative to anhydrous substance. Cld: C,30.76; H, 2.58; F, 39.39; Gd, 9.59; N, 5.98. Fnd: C, 30.87; H, 2.65; F,39.51; Gd, 9.69; N, 6.11.

EXAMPLE 25 Gadolinium complex, sodium salt of3,9-bis(carboxymethyl)-6-[N-(1H,1H,2H,2H-perfluorodecyl)-aminocarbonylmethyl-3,6,9-triazaundecanedioicacid a) N-Benzyloxycarbonylglycine-N-(1H,1H,2H,2H-perfluorodecyl)-amide

7.877 g (15 mmol) of 1H,1H,2H,2H-perfluorodecylamine (J. Fluor. Chem.55, 85 (1991)) is dissolved in 70 ml of dichloromethane and mixed with1.726 g (15 mmol) of N-hydroxysuccinimide, 3.095 g (15 mmol) ofdicyclohexylcarbodiimide and 3.138 g (15 mmol) ofN-benzyloxycarbonylglycine (commercially available products, Bachem). Itis allowed to stir overnight, the dicyclohexylurea is filtered off,concentrated by evaporation, and the residue is subjected to columnchromatography on silica gel. Mixtures of dichloromethane and ethanolare used as eluant. The title compound is obtained as a solid.

Yield: 8.951 g (91.2% of theory)

Elementary analysis: Cld: C, 36.71; H, 2.31; F, 49.36; N, 4.28. Fnd: C,36.87; H, 2.39; F, 49.51; N, 4.37.

b) Glycine-N-(1H,1H,2H,2H-perfluorodecyl)-amide

7.594 g (10 mmol) of the compound that is produced under 28a) isdissolved in 150 ml of a mixture of tetrahydrofuran and ethanol at a 2:1ratio and hydrogenated in the presence of 0.25 g of Pearlman's catalyst(Pd 20%/C) until 224 ml of hydrogen is taken up. Catalyst is suctionedout, rewashed well with ethanol and evaporated to dryness. The titlecompound is obtained as an amorphous solid.

Yield: 6.21 g (99.3% of theory)

Elementary analysis: Cld: C, 25.37; H, 1.60; F, 56.84; N, 4.93. Fnd: C,25.28; H, 1.65; F, 56.92; N, 4.99.

c)3,9-Bis(t-butyloxycarbonylmethyl)-6-N-[1H,1H,2H,2H-perfluorodecyl)-aminocarbonylmethyl-3,6,9-triazaundecanedioicacid-di(t-butylester)

2.841 g (5 mmol) of the amine that is produced under 25b) and 3.875 g(11 mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-(bromoethyl)-amine areadded to a mixture of 10 ml of acetonitrile and 20 ml of phosphatebuffer of pH 8.0, and it is stirred intensively at room temperature for2 hours. Then, the buffer phase is separated, it is extracted with 10 mlof acetonitrile, and the latter is added to the organic phase. After 20ml of fresh buffer is added, it is stirred for 20 more hours at roomtemperature. The organic phase is separated, concentrated byevaporation, and the residue is dispersed between 100 ml of phosphatebuffer (pH 8.0) and 100 ml of ethyl acetate. The organic phase is washedwith saturated common salt solution, dried on sodium sulfate andconcentrated by evaporation. The title compound is purified bychromatography on silica gel. Dichloromethane with increasing additionof methanol is used as eluant. The title compound is obtained as aglass-like solid.

Yield: 4.161 g (78.3% of theory)

Elementary analysis: Cld: C, 45.20; H, 5.59; F, 30.39; N, 5.27. Fnd: C,45.35; H, 5.67; F, 30.47; N, 5.34.

d)3,9-Bis(carboxymethyl)-6-N-(1H,1H,2H,2H-perfluorodecyl)-aminocarbonylmethyl-3,6,9-triazaundecanedioicacid

4.783 g (4.5 mmol) of the compound that is produced under 25c) is addedto a mixture of 100 ml of trifluoroacetic acid/dichloromethane at a 2:1ratio. It is allowed to stir overnight at room temperature, thenevaporated to dryness, the remainder of trifluoroacetic acid is removedby codistillation with ethanol and taken up in 160 ml of a mixture ofwater, ethanol and chloroform (10:5:1). A pH of about 3 (pH constant) isset by adding ion exchanger IRA-67 (OH⁻ form). It is suctioned offquickly, concentrated by evaporation, and the title compound is obtainedas a vitreous solid.

Yield: 3.007 g (79.7% of theory)

Water content: 10.9%

Elementary analysis (relative to anhydrous substance): Cld: C, 34.38; H,3.25; F, 38.52; N, 6.68. Fnd: C, 34.29; H, 3.33; F, 38.65; N, 6.77.

e) Gadolinium complex, monosodium salt of3,9-bis(carboxymethyl)-6-N-(1H,1H,2H,2H-perfluorodecyl)-aminocarbonylmethyl)-3,6,9-triazaundecanedioicacid

2.823 g (3.0 mmol, relative to 10.9% water content) of the acid thatis-produced under Example 25d) is added to a mixture of 60 ml ofdistilled water and 30 ml of ethanol. 543.8 mg (1.5 mmol) of gadoliniumoxide is added in portions while being stirred and heated to 50° C.After addition is completed, it is stirred until dissolved. Then, the pHof the solution is adjusted to 7.2 by adding sodium hydroxide solution.The solution is concentrated by evaporation. In this case, strongfoaming occurs. The residue is codistilled twice with distilled water.The title compound is obtained as a vitreous solid.

Yield: 3.353 g (quant)

Water content: 9.2%

The elementary analysis is relative to anhydrous substance. Cld: C,28.41; H, 2.28; F, 31.83; Gd, 15.50; N, 5.52; Na, 2.27. Fnd: C, 28.51;H, 2.33; F, 31.76; Gd, 15.57; N, 5.46; Na, 2.35.

EXAMPLE 26 Gadolinium complex, disodium salt of3,6,9-tris(carboxymethyl)-4-[N-1H,1H,2H,2H-perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioicacid a)3,6,9-Tris-(t-butyloxycarbonylmethyl)-4-[4-(1H,1H,2H,2H-perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioicacid-di(t-butylester)

6.131 g (5 mmol) of3,6,9-tris(t-butyloxycarbonylmethyl)-4-(4-hydroxybenzyl)-3,6,9-triazaundecanedioicacid-di(t-butylester), produced according to PCT WO 88/07521, is addedto 50 ml of dry dimethylformamide, and it is mixed in portions with 150g (5 mmol) of sodium hydride (80% in oil) while being stirred and withexclusion of moisture. After dissolving is completed, it is mixed with3.092 g (5 mmol) of the tosylate that is produced under Example 7a). Itis stirred for 12 hours at 40° C. Then, it is poured into 500 ml of icewater, the product is taken up in dichloromethane, the organic solutionis washed with water, dried on sodium sulfate and evaporated to dryness.The residue is purified by chromatography on silica gel. A mixture ofdichloromethane, isopropanol, hexane at a 20:1:5 ratio is used aseluant.

The title compound is obtained as an amorphous solid.

Yield: 5.015 g (81.8% of theory)

Elementary analysis: Cld: C, 49.96; H, 5.92; F, 26.34; N, 3.43. Fnd: C,50.11; H, 6.00; F, 26.43; N, 3.38.

b)3,6,9-Tris(carboxymethyl)-4-[4-(1H,1H,2H,2H-perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioicacid

3.678 g (3 mmol) of the compound that is produced under Example 26a) isdissolved in 100 ml of a mixture of trifluoroacetic acid anddichloromethane at a 2:1 ratio, and it is stirred overnight at roomtemperature. It is evaporated to dryness, and the remainder oftrifluoroacetic acid is removed by codistillation with ethanol. Theresidue is taken up in 160 ml of a mixture of water, ethanol andchloroform (10:5:1). By adding ion exchanger IRA-67 (OH⁻ form), a pH ofabout 3 (constant pH) is set. It is quickly suctioned off, concentratedby evaporation, and the title compound is obtained as a vitreous solid.

Yield: 2.357 g (83.1% of theory)

Water content: 11.3%

The elementary analysis is relative to anhydrous substance. Cld: C,39.38; H, 3.41; F, 34.16; N, 4.44. Fnd: C, 39.52; H, 3.47; F, 34.32; N,4.36.

c) Gadolinium complex, disodium salt of3,6,9-tris(carboxymethyl)-4-[N-(1H,1H,2H,2H-perfluorodecyloxy)-benzyl]-3,6,9-triazaundecanedioicacid

3.145 g (3.0 mmol, relative to 11.3% water content) of the acid that isproduced under Example 26b) is added to a mixture of 60 ml of distilledwater and 30 ml of ethanol. 543.8 mg (1.5 mmol) of gadolinium oxide isadded in portions while being stirred and heated to 50° C. Afteraddition is completed, it is stirred until dissolved. Then, the pH ofthe solution is adjusted to 7.2 by adding sodium hydroxide solution, andit is concentrated by evaporation. In this case, strong foaming occurs.The residue is codistilled twice with distilled water. The titlecompound is obtained as a vitreous solid.

Yield: 3.804 g (quantitative)

Water content: 9.8%

Elementary analysis (relative to anhydrous substance): Cld: C, 32.55; H,2.38; F, 28.24; Gd, 13.75; N, 3.67; Na, 4.02. Fnd: C, 32.44; H, 2.43; F,28.30; Gd, 13.66; N, 3.71; Na, 4.10.

EXAMPLE 27 Gadolinium complex of10-[(-perfluorooctyl-sulfonyl)-piperazin-1-yl-carbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecanea) 1-Perfluorooctylsulfonyl-piperazine

34.39 g (398.3 mmol) of piperazine, 50 g (99.6 mmol) ofperfluorooctylsulfonyl fluoride and 10.12 g (100 mmol) of triethylamineare heated for 24 hours to 85° C. 500 ml of water is added, and it isextracted twice with 200 ml of dichloromethane each. The organic phaseis dried on magnesium sulfate and evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:dichloromethane/2-propanol=25:1).

Yield: 17.55 g (31% of theory) of a colorless, amorphous solid

Elementary analysis: Cld: C, 25.36; H, 1.60; F, 56.84; N, 4.93; S, 5.64.Fnd: C, 25.15; H, 1.80; F, 56.65; N, 4.81; S, 5.70.

b) 1-(2-Bromoacetyl)-4-perfluorooctylsulfonyl-piperazine

17 g (29.9 mmol) of the title compound of Example 27a) and 5.1 g (50mmol) of triethylamine are dissolved in 100 ml of dichloromethane. 9.1 g(44.9 mmol) of bromoacetyl bromide is added in drops at −10° C. within30 minutes, and it is stirred for 2 hours at 0° C. The solution ispoured into 200 ml of 2N hydrochloric acid and stirred well. The organicphase is separated, dried on magnesium sulfate and concentrated byevaporation in a vacuum. The residue is chromatographed on silica gel(mobile solvent: dichloromethane/acetone=20/1).

Yield: 18.55 g (90% of theory) of a slightly yellow-colored waxy solid

Elementary analysis: Cld: C, 24.40; H, 1.46; F, 46.86; N, 4.06; S, 4.65;Br, 11.59. Fnd: C, 24.22; H, 1.60; F, 46.75; N, 3.97; S, 4.48; Br,11.41.

c)10-[(-Perfluorooctyl-sulfonyl)-piperazin-1-yl-carbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

4.63 g (13.36 mmol) of1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (≅D03A) and18.5 g (133.6 mmol) of potassium carbonate are added to 17.78 g (20mmol) of the title compound of Example 27b) in 180 ml of methanol. It isrefluxed for 12 hours. The inorganic salts are filtered off, and thefiltrate is evaporated to dryness. The residue is taken up in, 100 ml ofwater and adjusted to pH 3 with 5N hydrochloric acid. It is extractedtwice with 150 ml of n-butanol. The combined organic phases areevaporated to dryness in a vacuum, and the residue is purified byRP-chromatography (RP-18/mobile solvent=gradient consisting ofwater/n-butanol/acetonitrile).

Yield: 12.79 g (67% of theory) of a colorless solid

Water content: 8.5%

Elementary analysis (relative to anhydrous substance): Cld: C, 35.23; H,3.70; F, 33.83; N, 8.80; S, 3.36. Fnd: C, 35.17; H, 3.81; F, 33.67; N,8.65; S, 3.18.

d) Gadolinium complex of10-[(-perfluorooctyl-sulfonyl)-piperazin-1-yl-carbonylmethyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (10.47 mmol) of the title compound of Example 27c) is dissolved ina mixture of 50 ml of water/20 ml of ethanol, and 1.90 g (5.23 mmol) ofgadolinium oxide is added. It is stirred for 4 hours at 80° C. Thesolution is filtered and evaporated to dryness in a vacuum.

Yield: 12.2 g (quantitative)

Water content: 5.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 30.33; H,2.91; F, 29.13; Gd, 14.18; S, 2.89. Fnd: C, 30.39; H, 2.81; F, 29.02;Gd, 14.01; S, 2.78.

EXAMPLE 28 Gadolinium complex, monosodium salt of3,9-bis(carboxymethyl)-6-[(4-perfluorooctylsulfonyl)-piperazine-1-carbonylmethyl]-3,6,9-triazaundecanedioicacid a)1-(2-Benzyloxycarbonylamino)-methyl-carboyl-4-(perfluorooctylsulfonyl)-piperazine

8.524 g (15 mmol) of the piperazine derivative that is produced under27a) is dissolved in 80 ml of dichloromethane and mixed with 1.726 g (15mmol) of N-hydroxysuccinimide, 3.095 g (15 mmol) ofdicyclohexylcarbodiimide and 3.138 g (15 mmol) ofN-benzyloxycarbonylglycine (commercially available products, Bachem). Itis allowed to stir overnight, the dicyclohexylurea is filtered off,concentrated by evaporation, and the residue is subjected to columnchromatography on silica gel. Mixtures of dichloromethane and ethanolare used as eluant. The title compound is obtained as a solid.

Yield: 10.16 g (89.2% of theory)

Elementary analysis: Cld: C, 34.79; H, 2.39; F, 42.53; N, 5.53; S, 4.22.Fnd: C, 34.60; H, 2.43; F, 42.65; N, 5.66; S, 4.17.

b) 1-(2-Amino)-acetyl-4-(perfluorooctyl)-sulfonyl-piperazine

7.594 g (10 mmol) of the compound that is produced under 28a) isdissolved in 150 ml of a mixture of tetrahydrofuran and ethanol at a 2:1ratio, and it is hydrogenated in the presence of 0.25 g of Pearlman'scatalyst (Pd 20%/C) until 224 ml of hydrogen is taken up. Catalyst issuctioned out, rewashed well with ethanol and evaporated to dryness. Thetitle compound is obtained as an amorphous solid.

Yield: 6.21 g (99.3% of theory)

Elementary analysis: Cld: C, 26.89; H, 1.93; F, 51.65; N, 6.72; S, 5.13.Fnd: C, 27.03; H, 1.97; F, 51.77; N, 6.58; S, 5.20.

c)3,9-Bis(t-butyloxycarbonylmethyl)-6-[(4-perfluorooctylsulfonyl)-piperazine-1-carbonylmethyl]-3,6,9-triazaundecanedicarboxylicacid-di(t-butylester)

3.127 g (5 mmol) of the amine that is produced under 28b) and 3.875 g(11 mmol) of N,N-bis(t-butyloxycarbonylmethyl)-2-(bromoethyl)-amine areadded to a mixture of 10 ml of acetonitrile and 20 ml of phosphatebuffer of pH 8.0, and it is stirred intensively at room temperature for2 hours. Then, the buffer is separated, extracted with 10 ml ofacetonitrile, and the latter is added to the organic phase. After 20 mlof fresh buffer is added, it is stirred for 20 more hours at roomtemperature. The organic phase is separated, concentrated byevaporation, and the residue is dispersed between 100 ml of phosphatebuffer (pH 8.0) and 100 ml of ethyl acetate. The organic phase is washedwith saturated common salt solution, dried on sodium sulfate andconcentrated by evaporation. The title compound is purified bychromatography on silica gel. Dichloromethane with increasing additionof methanol is used as eluant. The title compound is obtained as aglass-like solid.

Yield: 4.481 g (76.3% of theory)

Elementary analysis: Cld: C, 43.71; H, 5.42; F, 27.99; N, 4.85; S, 2.78.Fnd: C, 43.84; H, 5.47; F, 28.10; N, 5.00; S, 2.69.

d)3,9-Bis(carboxymethyl)-6-[(4-perfluorooctyl-sulfonyl)-piperazin-1-yl-carbonylmethyl]-3,6,9-triazaundecanedioicacid

5.193 g (4.5 mmol) of the compound that is produced under 28c) is addedto a mixture of 100 ml of trifluoroacetic acid/dichloromethane at a 2:1ratio. It is allowed to stir overnight at room temperature, thenevaporated to dryness, the remainder of the trifluoroacetic acid isremoved by codistillation with ethanol and taken up in 160 ml of amixture of water, ethanol and chloroform (10:5:1). A pH of about 3(constant pH) is set by adding ion exchanger IRA-67 (OH⁻ form). It isquickly suctioned off, concentrated by evaporation, and the titlecompound is obtained as a vitreous solid.

Yield: 3.718 g (79.2% of theory)

Water content: 10.9%

Elementary analysis (relative to anhydrous substance): Cld: C, 33.59; H,3.25; F, 34.74; N, 6.03; S, 3.45. Fnd: C, 33.69; H, 3.36; F, 34.82; N,6.10; S, 3.38.

e) Gadolinium complex, monosodium salt of3,9-bis(carboxymethyl)-6-[(4-perfluorooctylsulfonyl)-piperazine-1-carbonylmethyl]-3,6,9-triazaundecanedioicacid

3.13 g (3.0 mmol, relative to 10.9% water content) of the acid that isproduced under Example 28d) is added to a mixture of 60 ml of distilledwater and 30 ml of ethanol. 543.8 mg (1.5 mmol) of gadolinium oxide isadded in portions while being stirred and heated to 50° C. Afteraddition is completed, it is stirred until dissolved. Then, the pH ofthe solution is adjusted to 7.2 by adding sodium hydroxide solution, andit is concentrated by evaporation. In this case, strong foaming occurs.The residue is codistilled twice with distilled water. The titlecompound is obtained as a vitreous solid.

Yield: 3.678 g (quantitative)

Water content: 9.2%

Elementary analysis (relative to anhydrous substance): Cld: C, 28.24; H,2.37; F, 29.21; Gd, 14.22; N, 5.07; Na, 2.08; S, 2.90. Fnd: C, 28.36; H,2.41; F, 29.14; Gd, 14.30; N, 5.15; Na, 2.12; S, 2.83.

EXAMPLE 29 Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis[(4-perfluorooctylsulfonyl)-piperazine]-amide a)3,6,9-Tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis[(4-perfluorooctylsulfonyl)-piperazine]-amide

5.683 g (10 mmol) of the compound that is produced under 27a) as well as1.518 g (15 mmol) of triethylamine are dissolved in 30 ml of drydimethylformamide and mixed in portions with 1.787 g (5 mmol) ofdiethylenetriaminepentaacetic acid-bisanhydride while being stirred andwith exclusion of moisture. It is allowed to stir overnight, thenconcentrated by evaporation, mixed with water, the pH is adjusted toabout 3 with 3N hydrochloric acid, and it is extracted twice with 100 mlof n-butanol each. The organic solutions are combined, concentrated byevaporation and subjected to a chromatography on silica gel RP-18. Waterand tetrahydrofuran are used as eluant. The title compound is obtainedas a glass-like solid.

Yield: 6.741 g (81.4% of theory)

Water content: 9.8%

Elementary analysis (relative to anhydrous substance): Cld: C, 30.55; H,2.50; F, 43.24; N, 6.56; S, 4.29. Fnd: C, 30.67; H, 2.55; F, 43.33; N,6.49; S, 4.21.

b) Gadolinium complex of3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioicacid-bis[(4-perfluorooctylsulfonyl)-piperazine]-amide

6.570 g (4 mmol, relative to 9.8% water content) of the compound that isproduced under 23c) is added to a mixture of 120 ml of distilled water,60 ml of ethanol and 20 ml of chloroform. While being stirred and heatedto 50° C., 725 mg (82.0 mmol) of gadolinium oxide is added in portions.It is stirred until dissolved, then concentrated by evaporation, wherebystrong foaming occurs, and the residue is subjected to codistillationwith distilled water. Codistillation is repeated twice. The titlecompound is obtained as a glass-like solid.

Yield: 7.191 g (quantitative)

Water content: 8.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 27.69; H,2.08; F, 39.19; Gd, 9.54; N, 5.95; S, 3.89. Fnd: C, 27.83; H, 2.15; F,39.10; Gd, 6.91; N, 6.03; S, 3.88.

EXAMPLE 30 a) 11-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]undecanoicacid benzyl ester

20 g (37.94 mmol) of N-ethyl-N-perfluorooctylsulfonamide and 15.73 g(113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone,and 26.96 g (75.87 mmol) of 11-bromoundecanoic acid benzyl ester isadded in drops at 60° C. It is stirred for 3 hours at 60° C. The saltsare filtered out, and the filtrate is evaporated to dryness in a vacuum.The residue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone=10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 26.46 g (87% of theory) of a colorless, crystalline powder

Elementary analysis: Cld: C, 41.95; H, 4.02; N, 1.75; F, 40.29; S, 4.00.Fnd: C, 41.78; H, 4.17; N, 1.68; F, 40.12; S, 3.88.

b) 11-[N-Ethyl-N-(perfluorooctylsulfonyl)-aminoundecanoic acid

20 g (24.95 mmol) of the title compound of Example 30a) is dissolved in300 ml of isopropanol/200 ml of dichloromethane, and 3 g of palladiumcatalyst (10% Pd/C) is added. It is hydrogenated overnight at roomtemperature. Catalyst is filtered out, and the filtrate is evaporated todryness in a vacuum. The residue is recrystallized from ether/hexane.

Yield: 16.69 g (94% of theory) of a colorless, crystalline solid.

Elementary analysis: Cld: C, 35.45; H, 3.68; N, 1.97; F, 45.39; S, 4.51.Fnd: C, 35.31; H, 3.81; N, 1.85; F, 45.25; S, 4.42.

c) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

12.16 g (17.09 mmol) of the title compound of Example 30b) and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C. and stirred for 1 hour at 0°C., then for 3 hours at room temperature. It is cooled again to 0° C.,and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol is added.Then, 10.78 g (18.79 mmol) of gadolinium complex of10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18/mobilesolvent: gradient of water/N-propanol/acetonitrile).

Yield: 16.82 g (71% of theory) of a colorless, vitreous solid.

Water content: 8.6%

Elementary analysis (relative to anhydrous substance): Cld: C, 36.02; H,4.30; F, 25.49; Gd, 12.41; N, 6.63; S, 2.53. Fnd: C, 35.87; H, 4.45; F,25.28; Gd, 12.29; N, 6.50; S, 2.41.

d)10-[2-Hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11.1 g (8.76 mmol) of the title compound of Example 30c) is dissolved ina mixture of 100 ml of water/100 ml of ethanol, and 1.73 g (13.71 mmol)of oxalic acid-dihydrate is added. It is heated for 8 hours to 80° C. Itis cooled to 0° C., and precipitated gadolinium oxalate is filtered out.The filtrate is evaporated to dryness, and the residue is purified onRP-18 (RP-18/mobile solvent: gradient consisting ofwater/i-propanol/acetonitrile).

Yield: 9.80 g (92% of theory) of a vitreous solid.

Water content: 8.5%

Elementary analysis (relative to anhydrous substance): Cld: C, 41.01; H,5.16; F, 29.02; N, 7.55; S, 2.88. Fnd: C, 40.87; H, 5.31; F, 28.85; N,7.40; S, 2.73.

e) Ytterbium complex of10-[2-hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

1.33 g (2.53 mmol) of ytterbium carbonate is added to 5.64 g (5.07 mmol)of the title compound of Example 30d) in 100 ml of water/50 ml ofethanol, and it is stirred for 3 hours at 80° C. The solution isfiltered, and the filtrate is evaporated to dryness in a vacuum.

Yield: 7.08 g (quantitative) of a vitreous solid.

Water content: 8.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 35.58; H,4.24; F, 25.17; N, 6.55; S, 2.50; Yb, 13.49. Fnd: C, 35.43; H, 4.37; F,25.05; N, 6.48; S, 2.39; Yb, 13.35.

f) Dysprosium complex of10-[2-hydroxy-4-aza-5-oxo-16-aza-16-(perfluorooctylsulfonyl-octadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

0.95 g (2.53 mmol) of dysprosium oxide is added to 5.64 g (5.07 mmol) ofthe title compound of Example 30d) in 100 ml of water/50 ml of ethanol,and it is stirred for 3 hours at 80° C. The solution is filtered, andthe filtrate is evaporated to dryness in a vacuum.

Yield: 7.10 g (quantitative) of a colorless, vitreous solid.

Water content: 9.1%

Elementary analysis (relative to anhydrous substance): Cld: C, 35.87; H,4.28; F, 25.38; N, 6.60; S, 2.52; Dy, 12.77. Fnd: C, 35.69; H, 4.39; F,25.18; N, 6.49; S, 2.43; Dy, 12.70.

EXAMPLE 31 a) 11,11,11,10,10,9,9,8,8,7,7-Tridecafluoro-3-oxaundecanoicacid-tert-butyl ester

19.51 g (100.0 mmol) of bromoacetic acid-tert-butyl ester is added indrops to a mixture of 27.57 g (75.73 mmol) of1H,1H,2H,2H-perfluorooctan-1-ol and 2.57 g (7.57 mmol) oftetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassiumhydroxide solution/200 ml of toluene while being stirred vigorously at0° C. It is stirred for one hour at 0° C., the organic phase isseparated, and the aqueous phase is extracted twice with 50 ml oftoluene. The combined organic extracts are dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel (mobile solvent: dichloromethane).

Yield: 28.97 g (80% of theory) of a colorless oil.

Elementary analysis: Cld: C, 35.16; H, 3.16; F, 51.64. Fnd: C, 35.08; H,3.20; F, 51.70.

b) 11,11,11,10,10,9,9,8,8,7,7-Tridecafluoro-3-oxaundecanoic acid

25.29 g (52.88 mmol) of the title compound of Example 1a) is dissolvedin 300 ml of trifluoroacetic acid, and it is stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum, and the residue isrecrystallized from hexane/diethyl ether.

Yield: 20.54 g (92% of theory) of a colorless, crystalline solid.

Elementary analysis: Cld: C, 28.45; H, 1.67; F, 58.51. Fnd: C, 28.36; H,1.60; F, 58.62.

c) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,15-tridecafluoro-pentadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

7.21 g (17.09 mmol) of the title compound of Example 31b and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18/mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 12.68 g (71% of theory) of a colorless, vitreous solid.

Water content: 6.4%

Elementary analysis (relative to anhydrous substance): Cld: C, 33.16; H,3.61; F, 25.26; Gd, 16.08; N, 7.16. Fnd: C, 32.85; H, 3.84; F, 25.01;Gd, 15.87; N, 7.03.

EXAMPLE 32 a)15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8-7,7-Henicosafluoro-3-oxapenta-decanoicacid-tert-butyl ester

19.51 g (100.0 mmol) of bromoacetic acid-tert-butyl ester is added indrops to a mixture of 42.72 g (75.73 mmol) of1H,1H,2H,2H-perfluorooctan-1-ol and 2.57 g (7.57 mmol) oftetrabutylammonium hydrogen sulfate in 300 ml of 60% aqueous potassiumhydroxide solution/200 ml of toluene while being stirred vigorously at0° C. It is stirred for one hour at 0° C., the organic phase isseparated, and the aqueous phase is extracted twice with 50 ml oftoluene. The combined organic extracts are dried on sodium sulfate andconcentrated by evaporation in a vacuum. The residue is chromatographedon silica gel (mobile solvent: dichloromethane).

Yield: 42.12 g (82% of theory) of a colorless oil.

Elementary analysis: Cld: C, 31.87; H, 2.23; F, 58.82. Fnd: C, 31.73; H,2.20; F, 58.90.

b)15,15,15,14,14,13,13,12,12,11,11,10,10,9,9,8,8,7,7-Henicosafluoro-3-oxapentadecanoicacid-tert-butyl ester

35.87 g (52.88 mmol) of the title compound of Example 1a) is dissolvedin 300 ml of trifluoroacetic acid, and it is stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum, and the residue isrecrystallized from hexane/diethyl ether.

Yield: 30.60 g (93% of theory) of a colorless, crystalline solid.

Elementary analysis: Cld: C, 27.03; H, 1.13; F, 64.12. Fnd: C, 26.91; H,1.20; F, 64.02.

c) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,18,18,19,19,19-henicosafluoro-nonadecyl]-1,4,7-tris(carboxymethyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10.63 g (17.09 mmol) of the title compound of Example 32b and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18/mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 14.73 g (69% of theory) of a colorless, vitreous solid.

Water content: 5.7%

Elementary analysis (relative to anhydrous substance): Cld: C, 31.61; H,2.99; F, 33.87; Gd, 13.35; N, 5.95. Fnd: C, 31.49; H, 3.15; F, 33.68;Gd, 13.21; N, 6.01.

EXAMPLE 33 a) N-(2-Bromopropionyl)glycine-benzyl ester

55.9 g (326.1 mmol) of 2-bromopropionic acid chloride is added in dropsto 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acidsalt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylenechloride at 0° C. The temperature is not allowed to exceed 5° C. Afterthe addition is completed, it is stirred for one hour at 0° C., then for2 hours at room temperature. 500 ml of ice water is added, and the waterphase is adjusted to pH 2 with 10% aqueous hydrochloric acid. Theorganic phase is separated and washed once each with 300 ml of 5%aqueous soda solution and 400 ml of water. The organic phase is dried onmagnesium sulfate and evaporated to dryness in a vacuum. The residue isrecrystallized from diisopropyl ether.

Yield: 68.51 g (75% of theory) of a colorless, crystalline powder

Melting point: 69-70° C.

Elementary analysis: Cld: C, 48.02; H, 4.70; N, 4.67; Br, 26.62. Fnd: C,47.91; H, 4.82; N, 4.51; Br, 26.47.

b)1-(4-(Benzyloxycarbonyl)-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane

50 g (162.2 mmol) of the title compound of Example 1a) is added to 55.8g (324.4 mmol) of 1,4,7,10-tetraazacyclododecane, dissolved in 600 ml ofchloroform, and it is stirred overnight at room temperature. 500 ml ofwater is added, the organic phase is separated, and it is washed twicewith 400 ml of water in each case. The organic phase is dried onmagnesium sulfate and evaporated to dryness in a vacuum. The residue ischromatographed on silica gel (mobile solvent:chloroform/methanol/aqueous 25% ammonia=10/5/1).

Yield: 40.0 g (63% of theory relative to 1a) used] of a light yellowishviscous oil.

Elementary analysis: Cld: C, 61.36; H, 8.50; N, 17.39. Fnd: C, 61.54; H,8.68; N, 17.68.

c)10-[4-(Benzyloxycarbonyl)-1-methyl-2-oxo-3-azabutyl]-1,4,7-tris(tert-butoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane(sodium bromide complex)

33 g (169 mmol) of bromoacetic acid-tert-butyl ester is added to 20 g(51.08 mmol) of the title compound of Example 1b) and 17.91 g (169 mmol)of sodium carbonate in 300 ml of acetonitrile, and it is stirred for 24hours at 60° C. It is cooled to 0° C., salts are filtered out, and thefiltrate is evaporated to dryness. The residue is chromatographed onsilica gel (mobile solvent: ethyl acetate/ethanol: 15/1). The fractionsthat contain the product are concentrated by evaporation, and theresidue is recrystallized from diisopropyl ether.

Yield: 34.62 g (81% of theory) of a colorless, crystalline powder

Melting point: 116-117° C.

Elementary analysis: Cld: C, 54.54; H, 7.59; N, 8.37; Na, 2.74; Br,9.56. Fnd: C, 54.70; H, 7.65; N, 8.24; Na, 2.60; Br, 9.37.

d)10-(4-Carboxy-1-methyl-2-oxo-3-azabutyl)-1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane(sodium bromide complex)

30 g (35.85 mmol) of the title compound of Example 1c is dissolved in500 ml of isopropanol, and 3 g of palladium catalyst (10% Pd/C) isadded. It is hydrogenated overnight at room temperature. Catalyst isfiltered out, the filtrate is evaporated to dryness in a vacuum andrecrystallized from acetone.

Yield: 22.75 g (85% of theory) of a colorless, crystalline powder

Melting point: 225° C. (decomposition)

Elementary analysis: Cld: C, 49.86; H, 7.69; N, 9.38; Na, 3.07; Br,10.71. Fnd: C, 49.75; H, 7.81; N, 9.25; Na, 2.94; Br, 10.58.

e)10-[1-Methyl-2-oxo-3-aza-5-oxo-5-{4-perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10 g (13.39 mmol) of the title compound of Example 33d and 7.61 g (13.39mmol) of the title compound of Example 27a are dissolved in 150 ml oftetrahydrofuran. 3.97 g (16.07 mmol) ofN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is added at 0° C.,stirred for 3 hours at 0° C., then for 12 hours at room temperature. Itis evaporated to dryness in a vacuum. The residue is taken up in 150 mlof trifluoroacetic acid and stirred for 12 hours at room temperature. Itis evaporated to dryness, the residue is dissolved in water and adjustedto pH 3.2 with 10% aqueous sodium hydroxide solution. For purification,it is chromatographed on RP-18 (gradient consisting ofwater/acetonitrile/tetrahydrofuran).

Yield: 9.67 g (63% of theory) of a hygroscopic solid.

Water content: 10.5%

Elementary analysis (relative to anhydrous substance): Cld: C, 36.30; H,3.93; N, 9.56; F, 31.49; S, 3.13. Fnd: C, 36.14; H, 3.98; N, 9.40; F,31.67; S, 3.02.

f) Gadolinium complex of10-[1-methyl-2-oxo-3-aza-5-oxo-5-(4-perfluorooctylsulfonyl-piperazin-1-yl}-pentyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

5 g (4.87 mmol) of the title compound of Example 33e is dissolved in 60ml of water, and 0.883 g (2.44 mmol) of gadolinium oxide is added. It isstirred for 3 hours at 90° C. The solution is filtered, and the filtrateis freeze-dried.

Yield: 6.47 g (quantitative) of a voluminous, amorphous powder

Water content: 11.3%

Elementary analysis (relative to anhydrous substance): Cld: C, 31.56; H,3.16; N, 8.31; F, 27.37; S, 2.72; Gd, 13.33. Fnd: C, 31.37; H, 3.35; N,8.18; F, 27.19; S, 2.92; Gd, 13.05.

EXAMPLE 34 a) 4-Perfluorooctanesulfonylpiperazin-1-ylpentanediamic acid

A solution of 10.62 g (105.0 mmol) of triethylamine and 59.67 g (105.0mmol) of the title compound of Example 27a) in 50 ml of tetrahydrofuranare added in drops to a suspension of 11.41 g (100.0 mmol) of glutaricanhydride in 100 ml of tetrahydrofuran while being stirred vigorously at0° C., and it is allowed to come to room temperature overnight. Thereaction mixture is acidified with 100 ml of 2N HCl and extracted threetimes with 100 ml of tetrahydrofuran. The combined organic extracts aredried with sodium sulfate, filtered and concentrated by evaporation. Theresidue is recrystallized from 2-propanol/ethyl acetate.

Yield: 52.30 g (73% of theory) of a colorless, crystalline solid.

Elementary analysis: Cld: C, 29.92; H, 2.22; N, 4.11; F, 47.33; S, 4.70.Fnd: C, 29.90; H, 2.18; N, 4.07; F, 47.42; S, 4.79.

b) Gadolinium complex of10-[2-hydroxy-4-aza-5,9-dioxo-9-{4-perfluorooctyl)-piperazin-1-yl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11.66 g (17.09 mmol) of the title compound of Example 34a and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C. and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxypropyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18/mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 16.7 g (73% of theory) of a colorless, vitreous solid.

Water content: 7.5%

Elementary analysis (relative to anhydrous substance): Cld: C, 32.99; H,3.50; F, 26.09; Gd, 12.70; N, 7.92; S, 2.59. Fnd: C, 32.75; H, 3.68; F,25.88; Gd, 12.55; N, 7.84; S, 2.63.

EXAMPLE 35 a) N-Benzylperfluorooctanesulfonamide

50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added indrops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.72 g(100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. Itis stirred for 2 days at 80° C., the reaction mixture is mixed with 300ml of water and extracted 3 times with ethyl acetate. The combinedorganic extracts are dried on sodium sulfate, filtered and concentratedby evaporation. The residue is chromatographed on silica gel (mobilesolvent: dichloromethane/methanol=4/1).

Yield: 45.96 g (78% of theory) of a colorless liquid

Elementary analysis: Cld: C, 30.57; H, 1.37; N, 2.38; S, 5.44; F, 54.81.Fnd: C, 30.49; H, 1.30; N, 2.42; S, 5.50; F, 54.90.

b) N-Benzyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl ester

22.4 g (37.94 mmol) of the title compound of Example 35a and 15.73 g(113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone,and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is addedin drops at 60° C. It is stirred for 3 hours at 60° C. Salts arefiltered out, and the filtrate is evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone=10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 24.02 g (90% of theory) of a waxy, colorless solid

Elementary analysis: Cld: C, 35.86; H, 2.58; N, 1.99; S, 4.56; F, 45.91.Fnd: C, 35.67; H, 2.71; N, 2.13; S, 4.45; F, 45.83.

c) N-Benzyl-N-(perfluorooctylsulfonyl)-aminoacetic acid

20 g (28.43 mmol) of the title compound of Example 35b is dissolved in200 ml of trifluoroacetic acid, and it is stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from methanol/ether.

Yield: 17.48 g (95% of theory) of a colorless, crystalline solid

Elementary analysis: Cld: C, 31.54; H, 1.56; N, 2.16; S, 4.95; F, 49.89.Fnd: C, 31.38; H, 1.70; N, 2.05; S, 4.87; F, 49.71.

d) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-8-phenyl-octyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11.06 g (17.09 mmol) of the title compound of Example 35c and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added and stirred for 3hours at room temperature. It is evaporated to dryness, the residue istaken up in a mixture of 200 ml of methanol/100 ml of chloroform, anddicyclohexylurea is filtered out. The filtrate is evaporated to drynessand purified by RP-chromatography (RP-18-mobile solvent: gradientconsisting of water/n-propanol/acetonitrile).

Yield: 16.49 g (75% of theory) of a colorless, vitreous solid

Water content: 6.5%

Elementary analysis: Cld: C, 33.95; H, 3.18; N, 6.99; S, 2.67; F, 26.85;Gd, 13.07. Fnd: C, 33.81; H, 3.24; N, 6.82; S, 2.54; F, 26.64; Gd,12.91.

EXAMPLE 36 a) N-Decylperfluorooctanesulfonamide

50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added indrops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 15.73 g(100.0 mmol) of decylamine at 80° C. while being stirred vigorously. Itis stirred for 2 days at 80° C., the reaction mixture is mixed with 300ml of water and extracted three times with ethyl acetate. The combinedorganic extracts are dried on sodium sulfate, filtered and concentratedby evaporation. The residue is chromatographed on silica gel (mobilesolvent: dichloromethane/methanol 4/1).

Yield: 43.48 g (68% of theory) of a colorless, viscous liquid

Elementary analysis: Cld: C, 33.81; H, 3.47; N, 2.19; S, 5.02; F, 50.51.Fnd: C, 33.71; H, 3.39; N, 2.15; S, 4.93; F, 50.31.

b) N-Decyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl ester

24.26 g (37.94 mmol) of the title compound of Example 36a and 15.73 g(113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone,and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is addedin drops at 60° C. It is stirred for 3 hours at 60° C. Salts arefiltered out, and the filtrate is evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone=10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 24.87 g (87% of theory) of a waxy, colorless solid

Elementary analysis: Cld: C, 38.25; H, 4.28; N, 1.86; S, 4.26; F, 42.86.Fnd: C, 38.09; H, 4.41; N, 1.74; S, 4.10; F, 42.67.

c) N-Decyl-N-(perfluorooctylsulfonyl)-aminoacetic acid

20 g (26.54 mmol) of the title compound of Example 36b is dissolved in200 ml of trifluoroacetic acid and stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from methanol/ether.

Yield: 17.22 g (93% of theory) of a colorless, crystalline solid

Elementary analysis: Cld: C, 34.44; H, 3.47; N, 2.01; S, 4.60; F, 46.31.Fnd: C, 34.28; H, 3.30; N, 1.95; S, 4.65; F, 46.28.

d) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-heptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

11.92 g (17.09 mmol) of the title compound of Example 36c and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled,again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18 mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 16.76 g (71% of theory) of a colorless, vitreous solid

Water content: 6.5%

Elementary analysis: Cld: C, 35.46; H, 4.18; N, 6.71; S, 2.56; F, 25.77;Gd, 12.55. Fnd: C, 35.28; H, 4.33; N, 6.80; S, 2.61; F, 25.65; Gd,12.41.

EXAMPLE 37 a) N-Hexylperfluorooctanesulfonamide

50.21 g (100.0 mmol) of perfluoroctanesulfonyl fluoride is added indrops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.12 g(100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. Itis stirred for 2 days at 80° C., the reaction mixture is mixed with 300ml of water and extracted three times with ethyl acetate. The combinedorganic extracts are dried on sodium sulfate, filtered and concentratedby evaporation. The residue is chromatographed on silica gel (mobilesolvent: dichloromethane/methanol=4/1).

Yield: 45.50 g (78% of theory) of a colorless liquid

Elementary analysis: Cld: C, 28.83; H, 2.42; N, 2.40; S, 5.50; F, 55.37.Fnd: C, 28.29; H, 2.39; N, 2.44; S, 5.55; F, 55.50.

b) N-Hexyl-N-(perfluorooctylsulfonyl)-aminoacetic acid-t-butyl ester

22.13 g (37.94 mmol) of the title compound of Example 37a and 15.73 g(113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone,and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is addedin drops at 60° C. It is stirred for 3 hours at 60° C. Salts arefiltered out, and the filtrate is evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone=10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 23.02 g (87% of theory) of a waxy, colorless solid

Elementary analysis: Cld: C, 34.44; H, 3.47; N, 2.01; S, 4.60; F, 46.31.Fnd: C, 34.31; H, 3.61; N, 1.97; S, 4.65; F, 46.25.

c) N-Hexyl-N-(perfluorooctylsulfonyl)-aminoacetic acid

20 g (28.43 mmol) of the title compound of Example 37b is dissolved in200 ml of trifluoroacetic acid, and it is stirred overnight at roomtemperature. It is evaporated to dryness in a vacuum. The residue isrecrystallized from methanol/ether.

Yield: 16.74 g (91% of theory) of a colorless, crystalline solid

Elementary analysis: Cld: C, 29.96; H, 2.51; N, 2.18; S, 5.00; F, 50.36.Fnd: C, 29.87; H, 2.70; N, 2.05; S, 4.84; F, 50.17.

d) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10.96 g (17.09 mmol) of the title compound of Example 37c and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18 mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 16.46 g (75% of theory) of a colorless, vitreous solid

Water content: 6.8%

Elementary analysis: Cld: C, 33.11; H, 3.70; N, 7.02; S, 2.68; F, 26.98;Gd, 13.14. Fnd: C, 33.01; H, 3.84; N, 6.95; S, 2.57; F, 26.85; Gd,13.03.

EXAMPLE 38 a) 11-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]-hexanoicacid benzyl ester

20 g (37.94 mmol) of N-ethyl-N-perfluorooctylsulfonylamide and 15.73 g(113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone,and 21.64 g (75.87 mmol) of 6-bromohexanoic acid benzyl ester is addedin drops at 60° C. It is stirred for 3 hours at 60° C. Salts arefiltered out, and the filtrate is evaporated to dryness in a vacuum. Theresidue is chromatographed on silica gel (mobile solvent:hexane/dichloromethane/acetone 10/10/1). After the product-containingfractions are concentrated by evaporation, the residue is recrystallizedfrom methanol/ether.

Yield: 25.26 g (91% of theory) of a colorless, crystalline powder

Elementary analysis: Cld: C, 37.77; H, 3.03; N, 1.91; S, 4.38; F, 44.15.Fnd: C, 37.61; H, 3.18; N, 1.84; S, 4.27; F, 44.01.

b) 11-[N-Ethyl-N-(perfluorooctylsulfonyl)-amino]-hexanoic acid

20 g (27.34 mmol) of the title compound of Example 38b is dissolved in300 ml of isopropanol/200 ml of dichloromethane, and 3 g of palladiumcatalyst (10% Pd/C) is added. It is hydrogenated overnight at roomtemperature. Catalyst is filtered out, and the filtrate is evaporated todryness in a vacuum. The residue is recrystallized from ether/hexane.

Yield: 16.13 g (92% of theory) of a colorless, crystalline solid

Elementary analysis: Cld: C, 29.96; H, 2.51; N, 2.18; S, 5.00; F, 50.36.Fnd: C, 29.81; H, 2.70; N, 2.09; S, 4.93; F, 50.14.

d) Gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-11-aza-11-(perfluorooctylsulfonyl)-tridecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane

10.96 g (17.09 mmol) of the title compound of Example 38b and 1.97 g(18.79 mmol) of N-hydroxysuccinimide are dissolved in a mixture of 50 mlof dimethylformamide/50 ml of chloroform. 3.88 g (18.79 mmol) ofdicyclohexylcarbodiimide is added at 0° C., and it is stirred for 1 hourat 0° C., then for 3 hours at room temperature. It is cooled again to 0°C., and 5.19 g (51.27 mmol) of triethylamine/50 ml of 2-propanol isadded. Then, 10.78 g (18.79 mmol) of the gadolinium complex of10-(3-amino-2-hydroxy-propyl)-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane(WO 95/17451), dissolved in 50 ml of water, is added, and it is stirredfor 3 hours at room temperature. It is evaporated to dryness, theresidue is taken up in a mixture of 200 ml of methanol/100 ml ofchloroform, and dicyclohexylurea is filtered out. The filtrate isevaporated to dryness and purified by RP-chromatography (RP-18 mobilesolvent: gradient consisting of water/n-propanol/acetonitrile).

Yield: 15.0 g (69% of theory) of a colorless, vitreous solid

Water content: 5.9%

Elementary analysis: Cld: C, 33.11; H, 3.70; N, 7.02; S, 2.68; F, 26.98;Gd, 13.14. Fnd: C, 33.01; H, 3.83; N, 6.91; S, 2.49; F, 26.83; Gd,13.05.

EXAMPLE 39

Blood Elimination Kinetics of Contrast Media

The blood elimination kinetics of contrast media was examined in rats(Han Wistar, Schering SPF, ≈250 g of body weight). For this purpose,after one-time intravenous administration (via a caudal vein) of thesubstances (dose: 50-100 μmol of Me per kg of body weight), thesubstance concentration in the blood (based on the Gd or Dy content) wasdetermined over a period of up to 300 minutes p.i. with the aid ofICP-AES. The pharmacokinetic parameters: distribution volume (Vss),total clearance (CLtot) and elimination half-life (tβ) were calculatedwith a special computer program (TOPFIT 2.0; Thomae, Schering, Gödecke),whereby a one- or two-compartment distribution model was used as abasis.

In comparison to Dy-DTPA (the dysprosium analogue of Magnevist®), thefluorine compounds according to the invention (e.g., Example 1c) showedconsiderably slower elimination from the blood and, in addition, asmaller distribution volume (see also FIG. 1 and Table 1).

It has been determined, surprisingly enough, that these compounds havean extended retention in the blood space and therefore are suitable as“blood pool contrast media”—e.g., for the visualization of blood vesselswith suitable techniques—even at relatively small dosages of ≦50 μmol ofGd per kg of body weight.

FIG. 1:

Elimination from the blood (in % of the injected dose) of Dy-DTPA (dose:100 μmol of Dy per kg of body weight, n=3) and of the fluorine compoundsof Example 1c according to the invention (dose: 50 μmol of Gd per kg ofbody weight, n=2) after one-time intravenous administration ofsubstances in rats (Han Wistar, Schering SPF, ≈250 g of body weight).

The Gd and Dy contents in the blood were determined with the aid ofICP-AES.

[Key to Table:]

% der injizierten dosis=% of injected dose

Beispiel 1c=Example 1c TABLE 1 Pharmacokinetic parameters: distributionvolume (Vss) , total clearance (CLtot) and elimination half-life (tβ) ofDy-DTPA and the fluorine compounds of Example 1c according to theinvention (calculated with TOPFIT 2.0; one- or two-compartment model).Vss (l/kg) CLtot(ml/(min · kg)) tβ (min) MEAN SD MEAN SD MEAN SD Dy-DTPA0.17 0.00 9.27 0.60 14.98 0.73 Example 0.14 0.02 1.07 0.09 95.01 10.371cFor further details see text for FIG. 1

EXAMPLE 40

Lymph Node Concentration in Guinea Pigs

Various fluorine-containing gadolinium and manganese complexes wereexamined 90 minutes to 24 hours after subcutaneous administration(2.5-10 μmol of total gadolinium/kg of body weight, hind paw s.c.)-tostimulated guinea pigs (complete Freund's adjunct; 0.1 ml i.m.respectively in the right and left thigh and lower leg: 2 weeks beforeadministration of test substances) to determine their lymph nodeconcentration in three successive lymph node stations (popliteal,inguinal, iliac). In this case, the results (determination of gadoliniumconcentration with the aid of ICP-AES) that are listed below in Table 2were obtained: TABLE 2 Sub- Time of Gadolinium or manganeseconcentration stance lymph in three successive lymph node stations Ex-node [μmol/l] ample removal [% dose/g of tissue] No. (dose) poplitealinguinal iliac ratio 1c) 4 h 120 μmol/l  29 μmol/l  40 μmol/l 10:2.4:3.3(2.5 μmol/kg)  17.2% 4.2% 5.6% 2c) 4 h 435 μmol/l  84 μmol/l 150 μmol/l10:2.0:3.5 (10 μmol/kg) 10.5% 2.0% 3.6% 1e) 90 min 559 μmol/l 224 μmol/l290 μmol/l 10:4.0:5.2 (10 μmol/kg)   15% 6.0% 7.8% 3c) 90 min 880 μmol/l277 μmol/l 339 μmol/l 10:3.1:3.9 (10 μmol/kg) 21.4% 6.7% 8.3%

EXAMPLE 41

Lymph Node Visualization (MRT) after Interstitial Administration of theContrast Medium

FIG. 1 shows MR recordings of popliteal and inguinal lymph nodes bothbefore (left side: precontrast) and 120 minutes after (right side)subcutaneous administration (guinea pigs, hind paw, interdigital space)of the Gd complex of Example 2c (referred to in the figure asGd-D03A-γ-aminoamide-perfluorooctylether) (10 μmol of Gd/kg of bodyweight). The T¹-weighted spin echo recordings (TR 400 ms, TE 15 ms)illustrate the strong signal rise in the popliteal and inguinal lymphnodes of the injected side of the body (straight arrow) in comparison tothe non-injected side of the body (curved arrow), or to the precontrastimage.

EXAMPLE 42

Elimination of the Contrast Medium after i.p. Administration

After administration of a perfluorinated gadolinium complex according tothe invention (100 μmol of total gadolinium/kg of body weight) in theintraperitoneal space of rats, the retention of metal in the liver aswell as in the remainder of the body was examined 14 days afteradministration. In this test, fluorine-containing compound 2c) was used.After 14 days p.i., the gadolinium concentration was 0.22% of theadministered dose in the liver and 1.1% of the administered dose in theremainder of the body.

In comparison with this, Gd-DPTA-polylysine as polymeric material is notcompletely eliminated. After 14 days, the body still contains 7% of theoriginal dose.

EXAMPLE 43

Determination of T¹-Relaxivity of Selected Compounds

The relaxivity of the following compounds was determined with a Minispecpc 20 (20 MHz, 0.47 T) at 37° C. in water and human plasma and comparedto that of Gd-DTPA-polylysine and Magnevist® as comparison substances.TABLE 3 R¹ [L/mmol*sec] Substance at 0.47 T and 37° C. Example No. WaterPlasma  1c) 41 49  2c) 19 33  3c) 15.2 27.5 22f) 6.9 20.5 30c) 21.1 26.931c) 5.2 29.1 32c) 19.4 24.8 33f) 31.5 35.7 34b) 25.9 24.9 35d) 23.134.0 37d) 19.9 n.m. 38c) 23.3 30.5 Comparison substances:Magnevist^((R)) 3.8 4.8 Gd-DTPA-polylysine¹⁾ 13.1 16.8¹⁾from Invest. Radiol. 1992, 346n.m. = not measured

1-17. (canceled)
 18. A method of imaging lymph nodes, comprisingconducting said imaging in conjunction with administration of a contrastagent comprising a perfluoroalkyl-containing compound of formula IR^(F)-L-A   I in which R^(F) is a perfluorinated, straight-chain orbranched carbon chain with formula —C_(n)F_(2n)X, in which X representsa terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and nstand for numbers 6-10, L means a direct bond, a methylene group, an—NHCO group, a group

whereby p means numbers 0 to 10, q and u, independently of one another,mean numbers 0 or 1 and R¹ is a hydrogen atom, a methyl group, a —CH₂—OHgroup, a —CH₂—CO₂H group or a C₂-C₁₅chain, which optionally isinterrupted by 1 to 3 oxygen atoms, 1 to 2 >CO groups or an optionallysubstituted aryl group and/or is substituted with 1 to 4 hydroxylgroups, 1 to 2 C₁-C₄ alkoxy groups, 1 to 2 carboxy groups, a group—SO₃H, or L is a straight-chain, branched, saturated or unsaturatedC₂-C₃₀ carbon chain, which optionally contains 1 to 10 oxygen atoms, 1to 3 —NR¹ groups, 1 to 2 sulfur atoms, a piperazine, a —CONR¹ group, an—SO₂ group, an —NR¹—CO₂ group, 1 to 2 —CO groups, a group—CO—N-T-N(R¹)—SO₂—R^(F) or 1 to 2 optionally substituted aryls and/or isinterrupted by these groups and/or is optionally substituted with 1 to 3—OR¹ groups, 1 to 2 oxo groups, 1 to 2 —NH—COR¹ groups, 1 to 2 —CONHR¹groups, 1 to 2 —(CH₂)_(p)—CO₂H groups, 1 to 2 groups of—(CH₂)_(p)—(O)_(q)—CH₂CH₂—R^(F), whereby R¹, R^(F) and p and q have theabove-indicated meanings, and T means a C₂-C₁₀ chain, which optionallyis interrupted by 1 to 2 oxygen atoms or 1 to 2 —NHCO groups, A standsfor a complexing agent or metal complex or their salts of organic and/orinorganic bases or amino acids or amino acid amides, specifically for acomplexing agent or complex of general formula II

in which R³, Z¹ and Y are independent of one another, and R³ has themeaning of R¹ or means —(CH₂)_(m)-L-R^(F), whereby m is 0, 1 or 2 and Land R^(F) have the above-mentioned meaning, Z¹ independently of oneanother, mean a hydrogen atom or a metal ion equivalent of atomicnumbers 21-29, 39, 42, 44 or 57-83, Y means —OZ¹ or

whereby Z¹, L, R^(F) and R³ have the above-mentioned meanings, or Astands for a complexing agent or complex of general formula III

in which R³ and Z¹ have the above-mentioned meanings and R² has themeaning of R¹, or A stands for a complexing agent of complex of generalformula IV

in which Z¹ has the above-mentioned meaning, or A stands for acomplexing agent or complex of general formula V

in which Z¹ has the above-mentioned meaning, and o and q stand fornumbers 0 or 1 and the sum o+q=1 results, or A stands for a complexingagent or complex of general formula VI

in which Z¹ has the above-mentioned meaning or A stands for a complexingagent or complex of general formula VII

in which Z¹ and Y have the above-mentioned meanings or A stands for acomplexing agent or complex of general formula VIII

in which R³ and Z¹ have the above-mentioned meanings, and R² has theabove-mentioned meaning of R¹, or A stands for a complexing agent orcomplex of general formula IX

in which R³ and Z¹ have the above-mentioned meanings, or A stands for acomplexing agent or complex of general formula X

in which R³ and Z¹ have the above-mentioned meanings, or A stands for acomplexing agent or complex of general formula XI

in which Z¹, p and q have the above-mentioned meaning and R² has themeaning of R¹, or A stands for a complexing agent or complex of generalformula XII

in which L, R^(F) and Z¹ have the above-mentioned meanings, or A standsfor a complexing agent or complex of general formula XIII


19. A method according to claim 18, wherein Z¹ stands for a hydrogenatom.
 20. A method according to claim 18, wherein X in formula—C_(n)F_(2n)X means a fluorine atom.
 21. A method according to claim 18,wherein L stands for

s stands for numbers 3-15; and t stands for numbers 2-6.
 22. A methodaccording to claim 18, wherein the contrast agent is gadolinium complexof10-[2-hydroxy-4-aza-5-oxo-7-aza-7-(perfluorooctylsulfonyl)-nonyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane;or gadolinium complex of10-[2-hydroxy-4-aza-5-oxo-7-oxa-10,10,11,11,12,12,13,13,14,14,15,15,16,16,17,17,17-heptadecafluoroheptadecyl]-1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane.